Quinolinecarboxylic acid derivatives

ABSTRACT

Quinolinecarboxylic acid derivatives represented by the following formula: ##STR1## wherein C is hydroxymethyl, methoxy, ethoxy or morpholinyl, or pharmaceutically acceptable salts thereof exhibit a potent action for stimulating a serotonin 4 receptor. The compounds exhibit an action of enhancing the gastrointestinal motor function to improve the gastrointestinal conditions such as heartburn, anorexia, bowel pain, abdominal distension, etc., accompanied by chronic gastritis, diabetes mellitus or postoperative gastroparesis, and are thus effective for the treatment of gastro-esophagal reflux, intestinal pseudo-obstruction and constipation.

TECHNICAL FIELD

The present invention relates to a quinolinecarboxylic acid derivative.More particularly, the present invention relates to a novelquinolinecarboxylic acid derivative, which has an action for stimulatinga serotonin 4 receptor. The present invention also relates to apharmaceutical use of such a quinolinecarboxylic acid derivative and anintermediate thereof.

BACKGROUND ART

Serotonin is a neurotransmitter which is widely distributed in human andhas a remarkable variety of physiological effects. It is hitherto knownthat serotonin receptors include three subtypes of serotonin 1 receptor,serotonin 2 receptor and serotonin 3 receptor. In addition to thesereceptors, the existence of serotonin 4 receptor was reported by DUMUIS,A., et al., see Molecular Pharmacology, 34, 880, 1988.

The Serotonin 4 receptor forms a conjugate with a G(Gs) protein toaccelerate an adenylate cyclase activity, cf., DUMUIS, A., et al.,supra. It is suggested that the receptor is located prejunctionally andpromotes the release of acetylcholine through cyclic AMP-dependent blockof K channel see RIZZI, C. A. et al., J. Pharmacol. Exp. Ther., 1992,412-419 (1992).

In the central nervous system, a localization of the serotonin 4receptor is observed on a high level in the striatum, hippocampus,substantia nigra, olfactory tubercle, etc. but with low concentrationsin the cerebral cortex, see GROSSMAN, C. J. et al., Br. J. Pharmacol.,109, 618-624 (1993). There are some reports on smooth muscle relaxation(REEVES, K. Y. et al., Br. J. Pharmacol., 103, 1067-1072 (1991)) and onthe cardiovascular effects in both human and pig (BOM, A. H. et al., Br.J. Pharmacol., 93, 663-671 (1988); VILLALON, C. M., et al., ibid., 100,665-667 (1990); and EGLEN, R. M. et al., ibid., 101, 513-520 (1990)).

In the gut, it is reported that the various actions through theserotonin 4 receptors are observed to show cholinergic nerve-mediatingcontraction in the guinea pig ileum and in the proximal colon (KAUMANN,A. J. et al., Br. J. Pharmacol., 100, 879-885 (1990) and ELSWOOD, C. L.et al., Eur. J. Pharmacol., 196, 149-155 (1991)), a potentiation ofelectrical field stimulation in the guinea pig ileum (CRAIG, D. A. etal., Br. J. Pharmacol. Exp. Ther., 252, 1378-1386 (1990)), an inductionof chloride secretion in rat distal colon (BUNCE, K. T. et al., Br. J.Pharmacol., 102, 811-816 (1991).

These results suggest that the serotonin 4 receptor present in the gutwould take a part in the induction and maintenance of gastrointestinalmotility and serotonin 4 receptor stimulants would activate thegastrointestinal motor function to exhibit the action of treating andimproving the gastrointestinal dysfunctions or conditions accompanied bymotility failure. In fact, cisapride and renzapride, which are effectivefor stimulating the serotonin 4 receptor, are reported to accelerate thegastrointestinal motor function and improve the gastrointestinalconditions such as heartburn, anorexia, bowel pain, abdominaldistension, etc., accompanied by chronic gastritis, diabetes mellitus orpostoperative gastroparesis, and are thus effective for the treatment ofgastro-esophagal reflux, intestinal pseudo-obstruction and constipation,see TALLEY, N. J., Alimentary Pharmacology and Therapeutics, 6, 273(1992).

As heterocyclic compounds which possess an activity of antagonizing orstimulating serotonin receptors, Japanese Patent Application Laid-OpenNo. 4-226980 (European Patent No. 0458636Al) discloses quinolinederivatives which antagonize serotonin 3 receptor. Serotonin 3 receptorantagonists are used to prevent nausea or vomiting induced by antitumoragents or upon radiotherapy. In addition, these antagonists suppress thegastrointestinal motility in the descending gut and are thus consideredto be effective for diarrhea-predominant irritable bowel syndrome.

On the other hand, Japanese Patent Application Laid-Open No. 3-197462(U.S. Pat. No. 5,106,851) discloses quinazolinecarboxylic acidderivatives as heterocyclic compounds that are effective for thetreatment of gastrointestinal disorders.

In the clinical field of gastrointestinal disorders, pirenzepine hasbeen made available as an anti-secretory and anti-ulcer agent whichfunctions as a muscarine 1 receptor antagonist. This is becausemuscarine 2 (or muscarine 3) is present in smooth muscles as themuscarine receptor so that its antagonizing action against thegastrointestinal motility is slight. However, in vitro studies indicatethat the muscarine 1 receptor antagonist does not act on any of thegastrointestinal motility but exhibits a slightly inhibitory action.This is because the muscarine 1 receptor exists on the myenteric gangliain the gut and considered to be participated in promotingneuro-transmission. It is therefore considered that the serotonin 3receptor antagonists and muscarine 1 receptor antagonists would be drugsexpected to exert the effect based on their function-inhibitingactivity, whereas the serotonin 4 receptor stimulants are expected toshow the function-promoting activity over the entire gastrointestinaltract.

As stated above, there is no report on such quinoline compounds havingan excellent antagonizing or stimulating activity particularly on theserotonin 4 receptor.

Accordingly, an object of the present invention is to provide a novelquinolinecarboxylic acid derivative having a potent stimulating activityespecially on the serotonin 4 receptor and a pharmaceutical use thereof.

DISCLOSURE OF INVENTION

The present inventors have made extensive studies to find a novelcompound for stimulating a serotonin 4 receptor. As a result, it hasbeen discovered that a certain quinolinecarboxylic acid derivativepossesses a potent serotonin 4 receptor-stimulating activity. By furtherinvestigations based on the discovery, the present invention has beenattained.

The present invention relates to a quinolinecarboxylic acid derivativerepresented by formula (A): ##STR2## wherein: X represents an oxygenatom or imino group;

m represents 0 or an integer of 1 to 6; and,

A represents an alkenyl group, an alkynyl group, a haloalkyl group,hydroxy group, an alkoxy group, an acyloxy group, an alkoxyalkoxy group,a mono- or di-alkylamino group, an alkylthio group, an alkylsulfinylgroup, an alkylsulfonyl group, an arylsulfonyl group, an aryloxy group,morpholinyl group, piperidyl group, tetrahydropyranyl group, analkoxycarbonyl group, carboxyl group, an alkanoyl group, cyano group orcarbamoyl group; or a pharmaceutically acceptable salt thereof.

The present invention also relates to the quinolinecarboxylic acidderivative or a pharmaceutically acceptable salt thereof for use in apharmaceutical composition.

The present invention further relates to use of the quinolinecarboxylicacid derivative or a pharmaceutically acceptable salt thereof for thepreparation of a pharmaceutical composition for stimulating a serotonin4 receptor.

The present invention further relates to a pharmaceutical compositionfor stimulating a serotonin 4 receptor which comprises as an effectiveingredient the quinolinecarboxylic acid derivative or a pharmaceuticallyacceptable salt thereof.

The present invention also relates to a method for stimulating aserotonin 4 receptor which comprises administering to human an effectivedose of the quinolinecarboxylic acid derivative or a pharmaceuticallyacceptable salt thereof.

The present invention further relates to a compound represented byformula (12): ##STR3## wherein L represents a halogen atom, an alkoxygroup having 1 or 3 or more carbon atoms, an aryloxy group, analkoxycarbonyloxy group, an acyloxy group, imidazolyl group or azidegroup, which is an intermediate for preparing the quinolinecarboxylicacid derivative or a pharmaceutically acceptable salt thereof.

The present invention further relates to a compound represented byformula (23): ##STR4## wherein X represents an oxygen atom or iminogroup; q represents an integer of 2 to 6; and D represents hydroxymethylgroup, an alkoxy group having 2 to 6 carbon atoms or morpholinyl group,or a salt thereof, which is an intermediate for preparing thequinolinecarboxylic acid derivative or a pharmaceutically acceptablesalt thereof.

BRIEF DESCRIPTION OF DRAWING

FIG. 1 is a graph showing the activity of the quinolinecarboxylic acidderivative of the present invention on the gastrointestinal motility inpostprandial state in dog.

BEST MODE FOR CARRYING OUT THE INVENTION

In the quinolinecarboxylic acid derivative represented by formula (A)above, examples of the group shown by A are given below. Specificexamples of the alkenyl group include an alkenyl group having 2 to 6carbon atoms such as vinyl, allyl, propenyl, 2-propenyl, butenyl,pentenyl and hexenyl. Specific examples of the alkynyl group include analkynyl group having 2 to 6 carbon atoms such as ethynyl, propargyl,butynyl and pentynyl. Specific examples of the haloalkyl group include ahaloalkyl group having 1 to 3 carbon atoms such as trifluoromethyl,trifluoroethyl and trichloromethyl. Specific examples of the alkoxygroup include an alkoxy group having 1 to 6 carbon atoms such asmethoxy, ethoxy, isopropoxy and t-butoxy. Specific examples of theacyloxy group include an acyloxy group having 2 to 8 carbon atoms suchas acetyloxy, propanoyloxy, butanoyloxy and hexanoyloxy. Specificexamples of the alkoxyalkoxy group are an alkoxyalkoxy group having 2 to8 carbon atoms such as methoxymethoxy, 2-methoxyethoxy,3-methoxypropoxy, 2-ethoxyethoxy, 3-ethoxypropoxy and 4-methoxybutoxy.Specific examples of the mono- or di-alkylamino group include a mono- ordi-alkylamino group having 1 to 6 carbon atoms such as monomethylamino,dimethylamino, monoethylamino, diethylamino, monopropylamino andmonobutylamino. Specific examples of the alkylthio group are analkylthio group having 1 to 6 carbon atoms such as methylthio,ethylthio, butylthio, propylthio and hexylthio. Specific examples of thealkylsulfinyl group include an alkylsulfinyl group having 1 to 6 carbonatoms such as methylsulfinyl, ethylsulfinyl, butylsulfinyl andhexylsulfinyl. Specific examples of the alkylsulfonyl group are analkylsulfonyl group having 1 to 6 carbon atoms such as methylsulfonyl,ethylsulfonyl, butylsulfonyl and hexylsulfonyl. Specific examples of thearylsulfonyl are an arylsulfonyl group having 6 to 12 carbon atoms suchas phenylsulfonyl, tolylsulfonyl and naphthylsulfonyl. Specific examplesof the aryloxy group are an aryloxy group having 6 to 12 carbon atomssuch as phenoxy, tolyloxy and naphthyloxy. Specific examples of thealkoxycarbonyl group are an alkoxycarbonyl group having 2 to 7 carbonatoms such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl andpropoxycarbonyl. Specific examples of the alkanoyl group include analkanoyl group having 2 to 8 carbon atoms such as methanoyl, ethanoyl,propanoyl, butanoyl and hexanoyl.

In the present invention, preferred are quinolinecarboxylic acidderivatives represented by formula (B): ##STR5## wherein X represents anoxygen atom or imino group; n represents an integer of 1 to 6; and Yrepresents hydroxy group, an alkoxy group, an alkanoyl group, analkoxycarbonyl group or morpholinyl group, or pharmaceuticallyacceptable salts thereof.

In formula (B), preferred examples of the alkoxy group, the alkanoylgroup and the alkoxycarbonyl group shown by group B are the same asthose given for group A in formula (A).

Particularly preferred are quinolinecarboxylic acid derivativesrepresented by formula (C): ##STR6## wherein Z represents hydroxymethyl,methoxy, ethoxy or morpholino group, or pharmaceutically acceptablesalts thereof.

Preferred examples of the pharmaceutically acceptable salts of thecompounds in accordance with the present invention are acid additionsalts obtained by adding pharmacologically acceptable acids thereto.

Specific examples of the acid addition salts are acid addition saltswith mineral acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; saltswith organic acids such as acetic acid, citric acid, tartaric acid,maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid,benzenesulfonic acid or methanesulfonic acid.

The pharmaceutically acceptable salts may also be in the form ofquaternary salt derivatives of the compounds shown by formula (A), whichare represented by the following formula: ##STR7## wherein X, A, R, mand Q have the same significance as defined above, and which may beobtained by reacting the compounds of formula (A) with compounds offormula (I):

    R--Q                                                       (I)

wherein R represents a lower alkyl group such as methyl, ethyl andpropyl; and Q represents a halogen atom such as fluorine, chlorine andbromine, or tosylate or mesylate.

The compounds of the present invention represented by formula (A) can beproduced, for example, by Preparation Scheme I or Preparation Scheme IIshown below. ##STR8##

In Preparation Schemes I and II, symbols X, A and m in the formulae havethe same significance as defined above and Q' in Compound (9) representsa leaving group such as a halogen atom (e.g., chlorine, bromine andiodine), tosylate or mesylate.

In Preparation Scheme I, the starting Compound (1) may be preparedaccording to the method described in J. Chem. Soc., 3462, 1960.

For the reductive ring closure from Compound (1) to Compound (2),reaction conditions for conventional reduction of a nitro group may beemployed. The reduction and ring closure take place simultaneously toobtain Compound (2). Examples of such reaction conditions for thereduction include:

(1) catalytic reduction in an appropriate solvent using a palladium-typecatalyst such as palladium-carbon, palladium black, palladium-bariumsulfate and palladium-calcium carbonate, or a platinum-type catalystsuch as platinum-carbon, platinum black, platinum oxide, etc., or anickel-type catalyst such as Raney nickel; and

(2) reduction in an appropriate inert solvent using iron or tin, orusing sodium sulfide-ammonium chloride.

The reduction in (1) above proceeds in a solvent and examples of thesolvent are water; acetic acid; an alcohol; a hydrocarbon such ashexane; an ether such as diethyl ether and tetrahydrofuran; anon-protonic polar solvent such as N,N-dimethylformamide; and a solventmixture thereof. As a solvent employed for the reduction in (2) above,examples include water, acetic acid, methanol, ethanol and dioxane, anda solvent mixture thereof.

The reaction temperature for the reduction in (1) and (2) is generallywithin the range from 0° C. to the boiling point of a solvent used; thereaction time is appropriately between 30 minutes and 24 hours.

Compound (2) is N-isopropylated to form Compound (3) under conditionsconventional for the N-alkylation of an acid amide. More specifically,the N-isopropylation is carried out in an appropriate solvent in thepresence of a reactive derivative for introducing the isopropyl groupand a base. Examples of the reactive derivative for introducing theisopropyl group include an isopropyl halide such as isopropyl iodide orisopropyl bromide. As the base employed, there are, for example, a metalalkali such as sodium and potassium; an alkali hydride such as sodiumhydride and potassium hydride; an alkali alkoxide such as sodiumethoxide and potassium t-butoxide; an alkali hydroxide such as sodiumhydroxide and potassium hydroxide; a carbonate such as sodium carbonateand potassium carbonate; an amine such as triethylamine,diisopropylethylamine, pyridine and N,N-dimethylaniline.

Examples of the solvent used for the N-isopropylation are water; analcohol such as methanol and ethanol; an ether such as diethyl ether,dioxane and tetrahydrofuran; a hydrocarbon such as hexane and benzene; anon-protic polar solvent such as N,N-dimethylformamide anddimethylsulfoxide; and a solvent mixture thereof. The reaction isperformed generally at 0° C. up to the boiling point of a solvent used.

In general, the reaction time is appropriately set for 30 minutes to 24hours.

Hydrolysis of Compound (3) to give Compound (4) is carried out underconventional conditions for hydrolysis, for example, acidic hydrolysisusing hydrochloric acid, hydrobromic acid, hydroiodic acid, acetic acidor sulfuric acid, or alkaline hydrolysis using sodium hydroxide,potassium hydroxide, sodium carbonate or potassium carbonate. Thereaction temperature is generally between 0° C. and the boiling point ofa solvent used. In general, the reaction time is appropriately set inthe range of 30 minutes to 24 hours.

Esterification or amidation of Compound (4) to Compound (7) is carriedout by reacting Compound (4) or its reactive derivative with tropine(Compound (5)) or with endo-3-amino-8-methyl-8-azabicyclo 3.2.1!octane(Compound (6)). Compound (6) can thus be prepared, see Journal ofAmerican Chemical Society, 79, 4194 (1957).

Examples of Compound (4) or its reactive derivatives are compoundsrepresented by formula (12): ##STR9## wherein L represents hydroxygroup, a halogen atom, an alkoxy group, an aryloxy group, analkoxycarbonyloxy group, an acyloxy group, imidazolyl group or azidegroup. Herein, the compounds of formula (12) other than those wherein Lis hydroxy or ethoxy are novel compounds that are obtained in thepresent invention for the first time.

In formula (12), specific examples of the groups shown by L are hydroxygroup; a halogen atom such as chlorine, bromine and iodine; an alkoxygroup having 1 to 6 carbon atoms such as methoxy and ethoxy; asubstituted or unsubstituted aryloxy group such as phenoxy,p-nitrophenoxy and pentachlorophenoxy; a C₂ -C₆ -alkoxycarbonyloxy groupsuch as ethoxycarbonyloxy; a C₂ -C₇ -acyloxy group such ast-butylcarbonyloxy or benzoyloxy; imidazolyl group and azide group.

The reactive derivative of Compound (4) represented by formula (12) maybe prepared, e.g., by the following process.

In order to prepare the reactive derivative wherein L is a halogen atom,Compound (4) is reacted with a halogenating agent such as oxalylchloride, thionyl chloride, phosphorus trichloride, phosphoruspentachloride or phosphorus tribromide.

As the solvent for the above reaction, there may be employeddichloroethane, chloroform, benzene, toluene, tetrahydrofuran orN,N-dimethylformamide. The reaction temperature is chosen from -20° C.to the boiling point of the solvent.

In order to obtain the reactive derivative (12) wherein L is an alkoxygroup, Compound (4) is reacted with an alcohol represented by formula(II):

    R.sup.1 --OH                                               (II)

wherein R¹ is an alkyl group.

The reaction may be carried out either in an appropriate solvent or inthe absence of any solvent. Where a solvent is employed, examples of thesolvent are toluene, xylene, benzene, n-hexane, tetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide, acetone, dichloromethane andchloroform. A catalyst may be used for the reaction; in this case, anacid catalyst such as hydrochloric acid, sulfuric acid orp-toluenesulfonic acid or a basic catalyst such as sodium methoxide,n-butyl lithium or sodium hydride may be employed. An appropriatetemperature for the reaction is within the range of -20° C. to theboiling point of the solvent used.

Specific examples of the solvent employed are toluene, xylene, benzene,n-hexane, ether, tetrahydrofuran, dimethylsulfoxide and chloroform. Anappropriate temperature for the reaction is within the range of -20° C.to the boiling point of the solvent used.

In order to obtain the reactive derivative (12) wherein L is an alkoxygroup, Compound (4) is reacted with a compound represented by formula(III):

    R.sup.4 --Q.sup.1                                          (III)

wherein R⁴ is an alkyl group and Q¹ represents chlorine, bromine,iodine, tosylate or mesylate, or with a sulfuric acid ester such as R⁴ ₂SO₄.

The reaction may proceed in an appropriate solvent and specific examplesof the solvent are toluene, xylene, benzene, n-hexane, tetrahydrofuran,dimethylsulfoxide, N,N-dimethylformamide, acetone and chloroform. Thereaction is carried out preferably in the presence of a base. Specificexamples of the base employed are sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate, potassium carbonate, triethylamine,diisopropylethylamine, pyridine and N,N-dimethylaniline. The temperatureis appropriately within the range of -20° C. to the boiling point of thesolvent employed.

The reactive derivative of formula (12) wherein L is an aryloxy group oran acyloxy group may be readily prepared in a conventional manner usedfor preparing an activated ester of carboxylic acid. The reactivederivative of formula (12) wherein L is an alkoxycarbonyloxy group,imidazolyl group or azide group may also be readily prepared in aconventional manner used for preparing a mixed anhydride, an activatedamide or an acid azide, respectively.

Where L is an active or unstable functional group, it is preferred touse the compound (12) wherein L is hydroxy, namely, a free carboxylicacid as Compound (4).

In Preparation Scheme I, the esterification or amidation betweenCompound (4) or its reactive derivative and Compound (5) or Compound (6)may be carried out in a conventional manner.

For example, there may be employed a method which comprises suitablyreacting the reactive derivative (12) of Compound (4) such as an acidhalide a lower alkyl ester or an activated ester, or its imidazolide ormixed anhydride with Compound (5) or Compound (6); or a method whichcomprises directly binding Compound (4) to Compound (5) or Compound (6)using a condensing agent.

Where the acid halide is employed, the halide is reacted with Compound(5) or Compound (6) generally in a solvent inert to the reaction at atemperature of from 0° C. to the boiling point of the solvent in thepresence of or absence of a base.

Examples of the solvent include ether, tetrahydrofuran, dioxane,methylene chloride, chloroform, dichloroethane, benzene, toluene,xylene, water or a mixture thereof.

Examples of the base which can be employed are sodium carbonate,potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium hydroxide, potassium hydroxide, pyridine,triethylamine, diisopropylethylamine, N,N-dimethylaniline, sodiumhydride and n-butyl lithium.

In general, the reaction time is appropriately in the range of 30minutes to 24 hours.

Where the reactive derivative (12) such as a lower alkyl ester or anactivated ester, or its imidazolide or mixed anhydride is reacted withCompound (5) or Compound (6), known reaction conditions conventionallyapplied may be used.

Where the compounds are directly bound to each other using a condensingagent, Compound (4) is reacted with Compound (5) or Compound (6)generally in a solvent inert to the reaction at a temperature of from 0°C. to the boiling point of the solvent used in the presence of acondensing agent.

Examples of the solvent include ether, tetrahydrofuran, dioxane,dichloromethane, chloroform, dichloroethane, benzene, toluene, xylene,water, or a mixture thereof.

Examples of the condensing agent which can be employed aredicyclohexylcarbodiimide, carbonyldiimidazole,2-chloro-N-methylpyridinium iodide, diphenylphosphorylazide, and diethylcyanophosphonate.

Next, the thus obtained Compound (7) is demethylated to give Compound(8) as shown in Preparation Scheme II. The demethylation may be effectedby a method using an alkyl haloformate such as chloroethylchloroformate, or by a method using bromocyanide, iodine orN-bromosuccinimide.

Then Compound (8) is reacted with Compound (9) in a solvent such aschloroform, ethanol, toluene, N,N-dimethylformamide, tetrahydrofuran ordimethylsulfoxide at a temperature of 0° C. to the boiling point of asolvent, in the presence or absence of a base. By the reaction, thequinolinecarboxylic acid derivative of the present invention representedby formula (A) can be finally prepared.

Where a base is employed, examples of the base include triethylamine,diisopropylethylamine, N,N-dimethylaniline, pyridine, sodium carbonate,potassium carbonate, sodium hydrogencarbonate and potassiumhydrogencarbonate. If necessary and desired, sodium iodide or potassiumiodide etc. may be used in addition to the base above.

Compound (8) may also be prepared by the following Preparation SchemeIII: ##STR10##

In Preparation Scheme III, symbols X and L have the same significance asdefined above and Boc represents t-butoxycarbonyl group.

As shown in Preparation Scheme III, Compound (10) is reacted with, e.g.,di-t-butyl dicarbonate to give Compound (11). A solvent is used for thereaction and examples of such a solvent include ether, tetrahydrofuran,dichloromethane, chloroform, toluene and benzene. The reactiontemperature is appropriately chosen from the range of -20° C. to theboiling point of the solvent.

Compound (11) may be converted into Compound (13) in a manner similar tothe conversion of Compound (4) into Compound (7) in Preparation SchemeI. Conversion of Compound (13) into Compound (8) is carried out by usinghydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid,trichloroacetic acid or trifluoroacetic acid in a solvent such as ether,tetrahydrofuran, dichloromethane, chloroform, toluene, benzene or ethylacetate.

The reaction temperature is appropriately chosen from the range of -20°C. to the boiling point of the solvent.

The compounds of the present invention may also be prepared according toPreparation Scheme IV below. ##STR11##

In Preparation Scheme IV, symbol X in formulae (23) and (17) has thesame significance as defined above; q represents an integer of 2 to 6;and D represents hydroxymethyl group, an alkoxy group having 2 to 6carbon atoms or morpholinyl group. Specific examples of these functionalgroups shown by D are the same as those given for group A in formula(A). R² in Compound (16) represents an alkyl group.

As shown in Preparation Scheme IV, Compound (17) of the presentinvention may also be prepared using as the starting compound2-isopropylaminobenzyl alcohol (14), which is prepared by the methoddescribed in Chem. Pharm. Bull., 34, 140 (1986).

Compound (15) can be prepared by oxidizing Compound (14) with anoxidizing agent under known conditions for oxidization. The oxidationmay be carried out in a solvent, using as an oxidizing agent atransition metal compound such as manganese dioxide, activated manganesedioxide or chromic acid; an organic compound such as dimethylsulfoxide,chloranil, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; lead tetraacetateor selenium dioxide. Examples of the solvent used are dioxane,tetrahydrofuran, ether, benzene, toluene, chloroform, water or a mixturethereof. The reaction temperature is appropriately chosen from the rangeof -20° C. to the boiling point of the solvent. In general, the reactiontime is appropriately between 30 minutes and 24 hours.

Compound (15) may also be obtained in the form of acid addition saltssuch as the hydrochloride.

Compound (15) may be converted into Compound (16) or Compound (4) bycondensing Compound (15) with malonic acid or a malonic acid ester inthe presence of or absence of a condensing agent.

Examples of the condensing agent which can be used include a hydroxide,carbonate, hydrogencarbonate, alcoholate and amide of an alkali metal;an amine such as ammonia and piperidine;, acetic acid, acetic anhydrideand zinc chloride. The condensing agents may be used alone or inadmixture. Compound (16) or Compound (4) may also be prepared byreacting with the condensing agent in a solvent such as benzene, tolueneor xylene or in the absence of a solvent. The reaction temperature isappropriately chosen from the range of -20° C. to the boiling point ofthe solvent. In general, the reaction time is appropriately between 30minutes and 24 hours.

Compound (17) of the present invention may be prepared by reactingCompound (4) or its reactive derivative with Compound (23) in the mannerdescribed above, for example, by the reaction between Compound (4) andCompound (5) or (6) in Preparation Scheme I, or by the reaction betweenCompound (11) and Compound (12) in Preparation Scheme III.

Compound (23) in Preparation Scheme IV may be prepared according toPreparation Scheme V shown below. ##STR12##

In Preparation Scheme V, symbols q, D and X have the same significanceas defined above; and R³ represents hydrogen, an alkyl group such asmethyl, or an alkanoyl group such as acetyl.

Compound (19) in Preparation Scheme V may be prepared by reactingCompound (18) with butanedial and 1,3-acetonedicarboxylic acid or itsester, by a modification of the method disclosed in Journal of OrganicChemistry, 22, 1385 (1957).

That is, butanedial obtained by treating 2,5-dimethoxytetrahydrofuranwith hydrochloric acid is reacted with Compound (18) and1,3-acetonedicarboxylic acid in a solvent to give Compound (19).Examples of the solvent used for the reaction are a hydrated solvent ofethanol, methanol, N,N-dimethylformamide or dimethylsulfoxide; andwater. The reaction temperature is appropriately chosen from the rangeof -20° C. to the boiling point of the solvent. In general, the reactiontime is appropriately between 30 minutes and 48 hours. It is preferredto adjust the reaction solution to an acidic region. Preferably thereaction is carried out by adjusting the pH to approximately 1.5 to 4.5,using, e.g., hydrochloric acid, sodium hydrogenphosphate or sodiumhydroxide.

Compound (20) is prepared by reacting Compound (19) with a hydroxylaminederivative represented by formula; R³ --O--NH₂, in a conventionalmanner. When Compound (20) is reduced in a conventional manner, forexample, reduction with sodium in an alcohol such as isoamyl alcohol;reduction with a hydride such as sodium borohydride, lithium aluminumhydride or borane; reduction in the presence of a palladium-typecatalyst such as palladium-carbon, palladium black, palladium-bariumsulfate and palladium-calcium carbonate, or in the presence of aplatinum-type catalyst such as platinum-carbon, platinum black, platinumoxide, etc., or in the presence of a nickel-type catalyst such as Raneynickel; whereby Compound (23) wherein X is imino is obtained.

Compound (23) wherein X is an oxygen atom may be prepared by directlyreducing Compound (19) in a manner similar to the reduction describedabove.

From the standpoint that Compound (23) is an intermediate for preparingpreferred quinolinecarboxylic acid derivatives of the present invention,Compound (23) is preferably represented by formula (24): ##STR13##wherein E represents hydroxymethyl, morpholino or ethoxy.

Compound (17) of the present invention may also be prepared by thefollowing Preparation Scheme VI. ##STR14##

In Preparation Scheme VI, symbols X, q and D have the same significanceas defined above.

Compound (22) may be prepared by condensing Compound (23) with malonicacid (21) or an ester thereof in a conventional manner, as shown inPreparation Scheme VI.

Examples of the solvent used for the condensation include hexane,benzene, toluene, xylene, tetrahydrofuran, dioxane,N,N-dimethylformamide and dimethylsulfoxide. The condensation may alsobe carried out in the absence of any solvent. The condensation mayproceed with or without a condensing agent. Where the condensing agentis employed, an acidic condensing agent such as hydrochloric acid,sulfuric acid, p-toluenesulfonic acid, phosphoric acid, or a basiccondensing agent such as sodium methoxide, n-butyl lithium or sodiumhydride may be employed.

An appropriate temperature for the reaction is within the range of -20°C. to the boiling point of the solvent used. In general, the reactiontime is appropriately between 30 minutes and 24 hours.

Compound (17) may be prepared by condensing Compound (22) with Compound(15) in the presence or absence of a condensing agent. Examples of thecondensing agent used include a hydroxide, carbonate, hydrogencarbonate,alcoholate and amide of an alkali metal; an amine such as ammonia andpiperidine;, acetic acid, acetic anhydride and zinc chloride. Thecondensing agents may be used alone or in admixture. Where it ispreferred to use a solvent, benzene, toluene or xylene may be used;alternatively, the condensation may proceed in the absence of anysolvent. The reaction temperature is appropriately chosen from the rangeof -20° C. to the boiling point of the solvent. In general, the reactiontime is appropriately between 30 minutes and 24 hours.

The thus obtained quinolinecarboxylic acid derivative or itspharmaceutically acceptable salt of the present invention acts onserotonin 4 receptor to exhibit a receptor-stimulating activity likeserotonin. That is, the compounds of the present invention acceleratethe gastrointestinal motor function and improve the gastrointestinalconditions such as heartburn, anorexia, bowel pain, abdominaldistension, etc., accompanied by chronic gastritis, diabetes mellitus orpostoperative gastroparesis, and are thus effective for the treatment ofgastro-esophagal reflux, intestinal pseudo-obstruction and constipation.

A dose of the compound of the present invention varies depending uponcondition. In general, a daily dose for adult is in the range of 0.1 to500 mg/human for oral administration and 0.01 to 100 mg/human forintravenous administration. The dose may be given at once or by dividingthe daily dose into several times.

The pharmaceutical composition of the present invention comprising thecompound of the present invention as an effective ingredient may beprepared into a solid preparation such as a tablet, a pill, a capsule orgranules, or into an injection, liquid, an emulsion or a suppository,and provided for use.

These pharmaceutical preparations may be provided by a known method forpreparing conventional pharmaceutical compositions. If necessary anddesired, an additive which is conventionally used may be added to thepreparations; examples of such an additive are an aid, a stabilizer, anemulsifier and a diluent.

Hereinafter the present invention will be described more specifically,by referring to Examples, Reference Examples and Experiments. Thenumbering of the compounds shown in the following Examples correspondsto that of the compounds used in Experiments.

EXAMPLE 1 Preparation of endo-N-(8-(2-propenyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 1)

Following the procedures shown in Preparation Scheme II, the titlecompound of formula (A) wherein X is imino, m is 1 and A is vinyl wasprepared.

(1) Endo-N-(8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride

A solution of 22.4 g of endo-N-(8-methyl-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide and6.85 ml of 1-chloroethyl chloroformate in 100 ml of 1,2-dichloroethanewas heated to reflux for an hour. After the solvent was distilled offunder vacuum, 100 ml of methanol was added to the residue. The mixturewas heated and stirred for an hour and then the solvent was distilledoff. The residue was recrystallized from isopropanol-ethyl acetate togive 24.3 g of endo-N-(8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride.

mp: >270° C.

(2) Endo-N-(8-(2-propenyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide

A solution of 1.11 g of endo-N-(8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride, 0.25 ml of 3-bromopropene and 1.2 g of potassiumcarbonate in 30 ml of ethanol was stirred at room temperature overnight.The reaction mixture was poured into water and extracted withchloroform. The chloroform layer was washed with water and dried oversodium sulfate. The solvent was distilled off and the residue waspurified by silica gel column chromatography (chloroform:methanol=20:1).Recrystallization from ethyl acetate gave 0.53 g ofendo-N-(8-(2-propenyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

mp: 126°-128° C. (ethyl acetate)

EXAMPLE 2

The following compounds were prepared in a manner similar to Example 1.

1) Endo-N-(8-(2-propynyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 2)

mp: 201°-203° C. (ethyl acetate)

2) Endo-N-(8-(2-hydroxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 4)

mp: 160°-162° C. (ethyl acetate)

3) Endo-N-(8-(3-hydroxypropyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 5)

mp: 171°-172° C. (ethyl acetate)

4) Endo-N-(8-(4-hydroxybutyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 6)

mp: 162°-164° C. (ethyl acetate)

5) Endo-N-(8-(5-hydroxypentyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 7)

NMR (ppm, CDCl₃); 1.68 (6H, d, J=7.2 Hz), 1.40-1.80 (7H, m), 1.85 (1H,s), 1.92 (1H, s), 2.10-2.30 (4H, m), 2.40-2.70 (4H, m), 3.40-3.60 (2H,m), 3.67 (2H, t, J=6.4 Hz), 4.35 (1H, q, J=7.0 Hz), 5.50-5.80 (1H, brs),7.22-7.35 (1H, m), 7.59-7.70 (2H, m), 7.75 (1H, d, J=7.8 Hz), 8.83 (1H,s), 10.55 (1H, d, J=7.2 Hz).

6) Endo-N-(8-(6-hydroxyhexyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride (Compound 8)

mp: 251°-253° C. (isopropanol)

7) Endo-N-(8-(5-acetoxypentyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride (Compound 9)

NMR (ppm, CDCl₃); 1.35-1.55 (2H, m), 1.61-1.80 (6H, d, J=7.0Hz), 1.68(6H, d, J=7.2 Hz), 2.05 (3H, s), 1.90-2.60 (8H, m), 2.70-2.95 (2H, m),3.02-3.35 (2H, m), 3.80-3.98 (2H, m), 4.07 (2H, t, J=6.4 Hz), 4.46 (1H,q, J=6.2 Hz), 5.40-5.80 (1H, brs), 7.26-7.38 (1H, m), 7.65 (1H, s), 7.67(1H, s), 7.77 (1H, d, J=7.8 Hz), 8.84 (1H, s), 10.65 (1H, d, J=6.4 Hz),12.05-12.35 (1H, brs).

8) Endo-N-(8-(2-ethoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 11)

mp: 99°-100° C. (isopropyl ether)

9) Endo-N-(8-(2-(2-methoxyethoxy)ethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride (Compound 14)

mp: 95°-97° C. (ethanol-isopropyl ether)

10) Endo-N-(8-(2-(methylthio)ethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 17)

mp: 168°-169° C. (ethyl acetate-isopropyl ether)

11) Endo-N-(8-(2-(methylsulfinyl)ethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 18)

mp: 177°-179° C. (ethyl acetate)

12) Endo-N-(8-(2-(phenylsulfonyl)ethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 19)

mp: 210°-211° C. (ethyl acetate)

13) Endo-N-(8-(2-(morpholinoethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 20)

mp: 177°-178° C. (ethyl acetate-isopropyl ether)

14) Endo-N-(8-(2-piperidinoethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 21)

mp: 159°-160° C. (ethyl acetate)

15) Endo-N-(8-(tetrahydropyran-2-methyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 22)

mp: 163°-164° C. (ethyl acetate)

16) Endo-N-(8-(2-phenoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 23)

mp: 146°-147° C. (ethyl acetate-isopropyl ether)

17) Endo-N-(8-((ethoxycarbonyl)methyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 25)

mp: 106°-108° C. (ethyl acetate-isopropyl ether)

18) Endo-N-(8-(carboxymethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 26)

mp: 244°-247° C. (methanol-ethyl acetate)

19) Endo-N-(8-(3-(ethoxycarbonyl)propyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride (Compound 27)

mp: 251°-252° C. (ethanol)

20) Endo-N-(8-(3-carboxypropyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 28)

mp: >250° C. (ethanol-ethyl acetate)

21) Endo-N-(8-acetyl-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 29)

mp: 208°-210° C. (ethyl acetate)

22) Endo-N-(8-(2-oxopropyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride (Compound 30)

mp: 208°-211° C. (decompd.) (ethanol)

23) Endo-N-(8-(4-oxopentyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 31)

mp: 101-103° C. (isopropyl ether-n-hexane)

24) Endo-N-(8-cyanomethyl-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 32)

mp: 178°-181° C. (ethyl acetate-isopropyl ether)

25) Endo-N-(8-(2-cyanoethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 33)

mp: 177°-178° C. (ethyl acetate-isopropyl ether)

26) Endo-N-(8-carbamoylmethyl-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 34)

mp: >250° C. (ethanol)

EXAMPLE 3 Preparation of endo-8-(2-propenyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 35)

Following the procedures shown in Preparation Scheme II, the titlecompound of formula (A) wherein X is an oxygen atom, m is 1 and A isvinyl was prepared.

(1) Endo-(8-azabicyclo 3.2.1!oct-3-yl)1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

A solution of 2.0 g of endo-(8-methyl-8-azabicyclo 3.2.1!oct-3-yl)1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate and 0.61 g of1-chloroethyl chloroformate in 50 ml of 1,2-dichloroethane was heated toreflux for an hour.

After the solvent was distilled off under vacuum, 30 ml of methanol wasadded to the residue. The mixture was heated and stirred for 30 minutesand the solvent was distilled off. The residue was purified by silicagel column chromatography (chloroform:NH3-saturated methanol=40:1).Recrystallization from isopropyl ether gave 1.60 g of endo-(8-azabicyclo3.2.1!oct-3-yl) 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate.

mp: 137°-140° C.

(2) Endo-8-(2-propenyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride

A solution of 170 mg of endo-(8-azabicyclo 3.2.1!oct-3-yl)1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate, 60 mg of allylbromide and 42 mg of potassium carbonate in 2 ml ofN,N-dimethylformamide was stirred at room temperature overnight.

Water was added to the reaction mixture. After extracting with ethylacetate, the organic layer was washed with saturated sodium chlorideaqueous solution and dried over anhydrous sodium sulfate. The solventwas distilled off and the residue was purified by alumina columnchromatography (chloroform).

The purified residue was dissolved in ethyl acetate and a 4Nhydrochloric acid-ethyl acetate solution was added to the solution. Thesolvent was distilled off to give 130 mg ofendo-8-(2-propenyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride.

NMR (ppm, CDCl₃); 1.65 (6H, d, J=8.0 Hz), 2.14 (1H, s), 2.27(1H, s),2.70-3.05 (3H, m), 3.05-3.25 (2H, m), 3.53 (2H, t, J=6.4 Hz), 3.87 (2H,s), 5.35-5.60 (3H, m), 6.30-6.55 (1H, m), 7.20-7.35 (1H, m), 7.55-7.80(3H, m), 8.31 (1H, s), 12.20-12.50 (1H, brs).

EXAMPLE 4

The following compounds were prepared in a manner similar to Example 3.

1) Endo-8-(2-propynyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide hydrochloride(Compound 36)

NMR (ppm, CDCl₃); 1.68 (6H, d, J=7.2 Hz), 2.25-2.35 (1H, m), 2.00-2.50(4H, m), 2.75-2.95 (2H, m), 3.10-3.30 (2H, m), 3.70-3.95 (2H, m),3.95-4.20 (2H, m), 5.30-5.65 (2H, m), 7.20-7.30 (1H, m), 7.55-7.71 (3H,m), 8.82 (1H, s), 12.70-12.95 (1H, brs).

2) Endo-8-(2-hydroxyethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 37)

mp: 191°-193° C. (ethanol-toluene)

3) Endo-8-(3-hydroxypropyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Compound 38)

mp: 129.5°-130.5° C. (ethyl acetate-isopropyl ether)

4) Endo-8-(4-hydroxybutyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 39)

mp: 209°-212.5° C. (ethanol-toluene)

5) Endo-8-(5-hydroxypentyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 40)

mp: 243°-245° C. (ethanol-toluene)

6) Endo-8-(6-hydroxyhexyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 41)

mp: 205°-207° C. (ethanol-isopropyl ether-toluene)

7) Endo-8-(2-methoxyethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 42)

NMR (ppm, CDCl₃); 1.65 (6H, d, J=7.0 Hz), 2.08-2.30 (4H, m), 2.70-2.82(2H, m), 3.08-3.30 (4H, m), 3.37 (3H, s), 3.90-4.12 (4H, m), 5.30-5.60(1H, brs), 5.41 (1H, t, J=4.4 Hz), 7.20-7.30 (1H, m), 7.55-7.70 (3H, m),8.30 (1H, s), 12.10-12.30 (1H, brs).

8) Endo-8-(2-ethoxyethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 43)

mp: 185.5°-187° C. (ethanol-isopropyl ether-toluene)

9) Endo-8-(2-(2-methoxyethoxy)ethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 59)

NMR (ppm, CDCl₃); 1.65 (6H, d, J=7.0 Hz), 2.11-2.20 (4H, m), 2.72-2.76(2H, m), 3.16-3.26 (4H, m), 3.38 (3H, s), 3.52-3.56 (2H, m), 3.65-3.70(2H, m), 4.06-4.16 (4H, m), 5.40-5.42 (2H, m), 7.21-7.29 (1H, m),7.60-7.67 (3H, m), 8.31 (1H, s), 12.13 (1H, brs).

10) Endo-8-(2-diethylaminoethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate dihydrochloride(Compound 44)

mp: 240.5°-242.5° C. (chloroform-ethyl acetate)

11) Endo-8-(2-(methylthio)ethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Compound 45)

mp: 130°-140° C. (ethyl acetate-isopropyl ether)

12) Endo-8-(2-(phenylsulfonyl)ethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Compound 46)

mp: 131°-133° C. (ethyl acetate-isopropyl ether)

13) Endo-8-(2-morpholinoethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinoline-carboxylate dihydrochloride(Compound 47)

mp: >270° C. (ethanol-chloroform)

14) Endo-8-(tetrahydropyran-2-methyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 48)

mp: 255°-256.5° C. (ethanol-toluene-isopropyl ether)

15) Endo-8-(2-phenoxyethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 49)

mp: 214.5°-217° C. (ethanol-toluene-isopropyl ether)

16) Endo-8-((ethoxycarbonyl)methyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 50)

mp: 191°-193.5° C. (ethanol-toluene-isopropyl ether)

17) Endo-8-(3-(ethoxycarbonyl)propyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 51)

NMR (ppm, CDCl₃); 1.26 (3H, t, J=7.0 Hz), 1.65 (6H, d, J=7.0 Hz),2.00-2.40 (6H, m), 2.40-2.60 (2H, m), 2.85-3.10 (2H, m), 3.10-3.30 (2H,m), 3.80-4.00 (2H, m), 4.14 (2H, q, J=7.0 Hz), 5.30-5.65 (2H, m),7.12-7.31 (1H, m), 7.50-7.70 (3H, m), 8.31 (1H, s), 11.80-12.10 (1H,brs).

18) Endo-8-(2-oxopropyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 52)

mp: 217°-225° C. (ethanol-toluene)

19) Endo-8-(4-oxopentyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 53)

mp: 230°-236° C. (ethanol-toluene-isopropyl ether)

20) Endo-8-(cyanomethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 54)

mp: 209°-213° C. (ethanol-toluene)

21) Endo-8-(2-cyanoethyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Compound 55)

mp: 132°-134° C. (ethyl acetate)

22) Endo-8-carbamoylmethyl-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Compound 56)

mp: 261.5°-264.5° C. (ethanol)

EXAMPLE 5 Preparation ofendo-N-(8-(1,1-dimethylethoxy)carbonyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 24)

Following the procedures shown in Preparation Scheme III, the titlecompound wherein X is imino in Compound (13) was prepared.

(1) 8-Benzyl-8-azabicyclo 3.2.1!octan-3-one oxime

To a solution of 65 ml of 2,5-dimethoxytetrahydrofuran in 200 ml ofwater was added 22 ml of conc. hydrochloric acid. The solution wasstirred at room temperature for 20 minutes.

Under chilling with water, 500 ml of water, 82 ml of benzyl amine, asolution of 75 ml of conc. hydrochloric acid in 500 ml of water, 80 g of1,3-acetonedicarboxylic acid, 44 g of Na₂ HPO₄ and 200 ml of watercontaining 7.3 g of sodium hydroxide were successively added to thereaction mixture. The resulting mixture was stirred overnight at roomtemperature. After 33 ml of conc. hydrochloric acid was added to thereaction mixture, the system was stirred for further 3 hours. Afterwashing with chloroform, 200 ml of water containing 75 g of sodiumhydroxide was added to the mixture. The mixture was then extracted withchloroform.

After drying, the solvent was distilled off to give 152 g of crude8-benzyl-8-azabicyclo 3.2.1!octan-3-one.

The crude product was dissolved in 200 ml of ethanol and 33 ml of 50%hydroxylamine aqueous solution was then added to the solution. Themixture was heated at 70° C. for 2 hours while stirring. The solvent wasdistilled off. Toluene was then added to the residue. Under reflux withheating, water was azeotropically removed. After the solvent wasdistilled off, the residue was recrystallized from ethanol to give 69.7g of 8-benzyl-8-azabicyclo 3.2.1!octan-3-one oxime.

MS (m/z); 230 (M⁺), 213, 158, 91.

NMR (ppm, CDCl₃); 1.45-1.75 (2H, m), 1.90-2.15 (2H, m), 2.14 (1H, d,J=16 Hz), 2.25 (1H, dd, J=16, 3 Hz), 2.63 (1H, dd, J=16, 3 Hz), 2.99(1H, d, J=16 Hz), 3.30-3.43 (2H, m), 3.65 (2H, s), 7.18-7.48 (5H, m),8.30-9.00 (1H, brs).

(2) 3-Amino-8-azabicyclo 3.2.1!octane

To a solution of 20.4 g of 8-benzyl-8-azabicyclo 3.2.1!octan-3-one oximein 100 ml of acetic acid was added 2.0 g of platinum oxide to performcatalytic hydrogenation under a hydrogen pressure of 5 kg/cm2 at 30°-35°C. for 10 hours.

After completion of the hydrogenation, insoluble matters were filteredoff and 40 ml of conc. hydrochloric acid was added to the filtrate. Thesolvent was distilled off under vacuum and the residue wasrecrystallized from ethanol to give 8.3 g of 3-amino-8-azabicyclo3.2.1!octane hydrochloride. After 8.3 g of the hydrochloride was addedto 100 ml of ethanol, a solution of 5.2 g of potassium hydroxide in 50ml of ethanol was added to the mixture followed by stirring at roomtemperature for 3 hours. Insoluble matters were filtered off and thesolvent was then distilled off to give 2.3 g of 3-amino-8-azabicyclo3.2.1!octane.

MS (m/z); 126 (M⁺), 110, 82, 68.

NMR (ppm, CDCl₃); 1.18-2.20 (11H, m), 3.28 (1H, t, J=7 Hz), 3.43-3.60(2H, m).

(3) 3-Amino-8-((1,1-dimethylethoxy)carbonyl)-8-azabicyclo 3.2.1!octane

To a solution of 1.5 g of 3-amino-8-azabicyclo 3.2.1!octane in 50 ml ofmethylene chloride was dropwise added a solution of 2.7 ml of di-t-butyldicarbonate in 5 ml of methylene chloride. The mixture was stirred atroom temperature for 4 hours. The solvent was distilled off and theresidue was subjected to silica gel column chromatography(chloroform:NH3-saturated methanol=40:1) to give 1.23 g of3-amino-8-((1,1-dimethylethoxy)carbonyl)-8-azabicyclo 3.2.1!octane.

NMR (ppm, CDCl₃); 1.46 (9H, s), 1.30-2.32 (10H, m), 3.31 (1H, t, J=7Hz), 4.00-4.39 (2H, brs).

(4) Endo-N-(8-((1,1-dimethylethoxy)carbonyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide

To a solution of 1.25 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid in 30 ml oftoluene was added 5 ml of thionyl chloride. The mixture was heated toreflux for 5 hours.

After the solvent was distilled off, 20 ml of toluene was added to theresidue. By performing distillation again, an excess of thionyl chloridewas removed. While vigorously agitating a mixture of 30 ml of watercontaining 1.5 g of sodium hydroxide and a solution of 1.2 g of3-amino-8-((1,1-dimethylethoxy)-carbonyl)-8-azabicyclo 3.2.1!octane in30 ml of methylene chloride, a solution of the acid chloride obtainedabove in 10 ml of methylene chloride was dropwise added to the mixtureunder ice cooling. Stirring was continued for further an hour.

After completion of the reaction, the reaction mixture was extractedwith methylene chloride. The organic layer was washed and then dried.The solvent was distilled off and the residue was recrystallized fromisopropyl ether to give 1.4 g ofendo-N-8-((1,1-dimethylethoxy)carbonyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

mp: 144°-146° C.

EXAMPLE 6 Preparation of endo-N-(8-(2-methoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride (Compound 10)

Following the procedures shown in Preparation Scheme V,endo-3-amino-8-(2-methoxyethyl)-8-azabicyclo 3.2.1!octane whichcorresponds to Compound (23) wherein X is imino, q is 2 and D is methoxywas prepared. Then, the resulting octane was reacted with Compound (4)in accordance with Preparation Scheme IV to give the title compound.

(1) Endo-8-(2-methoxyethyl)-8-azabicyclo 3.2.1!octan-3-one

To a solution of 65 ml of 2,5-dimethoxytetrahydrofuran in 200 ml ofwater was added 22 ml of conc. hydrochloric acid. The mixture wasstirred at room temperature for 20 minutes. Under chilling with water,500 ml of water, 65 ml of 2-methoxyethylamine, 770 ml of 10%hydrochloric acid aqueous solution, 80 g of 1,3-acetonedicarboxylicacid, 44.5 g of Na₂ HPO₄ and 200 ml of water containing 7.5 g of sodiumhydroxide were successively added to the reaction mixture. The resultingmixture was stirred overnight at room temperature. After 33 ml of conc.hydrochloric acid was added to the reaction mixture, the system wasstirred for further 6 hours.

After the reaction solution was washed with chloroform, 200 ml of watercontaining 75 g of sodium hydroxide was added to the reaction solution.The mixture was then extracted with chloroform. After drying, thesolvent was distilled off and the residue was subjected to silica gelcolumn chromatography (ethyl acetate:methanol=10:1). Distillation undervacuum gave 7.2 g of endo-8-(2-methoxyethyl)-8-azabicyclo3.2.1!octan-3-one.

bp: 139° C. (14 mmHg) IR ν (cm⁻¹, neat); 3401, 2953, 1713, 1349, 1122.

MS (m/z); 183 (M⁺), 138, 126, 96.

NMR (ppm, CDCl₃); 1.61 (2H, dd, J=14.5, 7.7 Hz), 1.98-2.12 (2H, m), 2.19(2H, d, J=16.7 Hz), 2.73 (2H, dd, J=17.6, 3.8 Hz), 2.83 (2H, t, J=5.6Hz), 3.39 (3H, s), 3.56-3.75 (4H, m).

(2) Endo-8-(2-methoxyethyl)-8-azabicyclo 3.2.1!octan-3-one oxime

After 2.9 g of 50% hydroxylamine aqueous solution was added to asolution of 4 g of -8-(2-methoxyethyl)-8-azabicyclo 3.2.1!octan-3-one in40 ml of ethanol, the mixture was stirred at room temperature for 2hours.

The solvent was distilled off and the residue was purified by silica gelcolumn chromatography (chloroform:methanol=20:1) to give 4.5 g of-8-(2-methoxyethyl)-8-azabicyclo 3.2.1!octan-3-one oxime.

NMR (ppm, CDCl₃); 1.38-1.73 (2H, m), 1.85-2.32 (4H, m), 2.53-2.67 (2H,m), 2.72 (2H, t, J=5.9 Hz), 2.89-3.05 (1H, m), 3.37 (3H, s), 3.39-3.51(2H, m), 3.57 (2H, t, J=5.9 Hz), 9.26 (1H, brs).

(3) Endo-3-amino-8-(2-methoxyethyl)-8-azabicyclo 3.2.1!octanedihydrochloride

To a solution of 4.5 g of endo-8-(2-methoxyethyl)-8-azabicyclo3.2.1!octan-3-one oxime in 40 ml of acetic acid was added 500 mg ofplatinum oxide to perform catalytic hydrogenation under a hydrogenpressure of 5 kg/cm² at 30°-35° C. for 10 hours.

After completion of the hydrogenation, insoluble matters were filteredoff and 6 ml of conc. hydrochloric acid was added to the filtrate. Thesolvent was distilled off. The residue was then dried and recrystallizedfrom ethanol to give 3.4 g ofendo-3-amino-8-(2-methoxyethyl)-8-azabicyclo 3.2.1!octanedihydrochloride.

mp: 266° C. (decompd.)

(4) Endo-N-(8-(2-methoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride

A solution of 700 mg of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid and 1.1 ml ofthionyl chloride in 15 ml of toluene was stirred for an hour withheating. After the solvent was distilled off, toluene was added to theresidue. After toluene was again distilled off, the residue wasdissolved in 10 ml of tetrahydrofuran.

Under ice cooling, the solution was dropwise added to 20 ml of 50%tetrahydrofuran aqueous solution containing 940 mg of3-amino-8-(2-methoxyethyl)-8-azabicyclo 3.2.1!octane dihydrochloride and650 mg of sodium hydroxide. The mixture was stirred at room temperaturefor 3 hours.

After completion of the reaction, the reaction mixture was diluted withwater. The dilution was extracted with ethyl acetate. The organic layerwas successively washed with water and saturated sodium chloride aqueoussolution, followed by drying over anhydrous sodium sulfate. The solventwas distilled off and the residue was subjected to silica gel columnchromatography (chloroform:methanol=9:1) to giveendo-N-(8-(2-methoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

The product was further dissolved in ethyl acetate and then, 4Nhydrochloric acid-ethyl acetate solution was added to the solution togive 760 mg of endo-N-(8-(2-methoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride.

m.p.; 247°-249° C.

NMR (ppm, CDCl₃); 1.68 (6H, d, J=7.0 Hz), 2.10 (1H, s), 2.18 (1H, s),2.25-2.60 (4H, m), 3.10-3.20 (2H, m), 3.20-3.30 (1H, m), 3.38 (3H, s),3.30-3.55 (1H, m), 3.95-4.18 (4H, m), 4.07 (1H, q, J=4.0 Hz), 5.30-5.80(1H, brs), 7.26-7.36 (1H, m), 7.65 (1H, s), 7.67 (1H, s), 7.77 (1H, d,J=7.6 Hz), 8.85 (1H, s), 10.68 (1H, d, J=6.6 Hz), 11.90-12.25 (1H, brs).

EXAMPLE 7

The following compounds were prepared in a manner similar to Example 6.

1) Endo-N-(8-(2,2,2-trifluoroethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidehydrochloride (Compound 3)

mp: 241.0°-244.0° C. (ethanol)

2) Endo-N-(8-(2-diethylaminoethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamidedihydrochloride (Compound 16)

mp: 179.0°-186.0° C. (ethanol-ethyl acetate-acetone)

Reference Example 1 Preparation of endo-8-(4-methoxyphenyl)-8-azabicyclo3.2.1!oct-3-yl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate(Compound 57)

For a reference example, the title compound corresponding to a compoundof formula (A) wherein X is an oxygen atom, m is 0 and A is4-methoxyphenyl was prepared.

(1) 8-(4-Methoxyphenyl)-8-azabicyclo 3.2.1!octan-3-one

To a solution of 36 ml of 2,5-dimethoxytetrahydrofuran in 100 ml ofwater was added 12 ml of conc. hydrochloric acid. The mixture wasstirred at room temperature for 20 minutes. Under chilling with water,200 ml of water, 50 g of 4-methoxyaniline, 43 ml of conc. hydrochloricacid, 43.5 g of 1,3-acetonedicarboxylic acid, 19.2 g of Na₂ HPO₄ and 3.9g of sodium hydroxide were successively added to the reaction mixture.The resulting mixture was stirred overnight at room temperature. After18 ml of conc. hydrochloric acid was added to the reaction mixture,stirring was continued for further 6 hours.

After the reaction solution was washed with chloroform, 30 ml of watercontaining 39 g of sodium hydroxide was added to the reaction solution.The mixture was then extracted with chloroform. After drying, thesolvent was distilled off and the residue was subjected to silica gelcolumn chromatography (chloroform:NH₃ -saturated methanol=100:1).Recrystallization from ethanol gave 6.75 g of8-(4-methoxyphenyl)-8-azabicyclo 3.2.1!octan-3-one.

mp: 133°-134° C.

(2) Endo-8-(4-methoxyphenyl)-8-azabicyclo 3.2.1!octan-3-ol

A solution of 4 g of 8-(4-methoxyphenyl)-8-azabicyclo 3.2.1!octan-3-onein 80 ml of tetrahydrofuran was cooled to -70° C. and 51 ml ofdiisobutyl aluminum hydride (1M tetrahydrofuran solution) was thendropwise added to the solution.

After completion of the reaction, 12 ml of 50% tetrahydrofuran aqueoussolution was added to the reaction mixture and insoluble matters werefiltered off. The solvent was distilled off and dried. Recrystallizationfrom ethyl acetate-n-hexane gave 1.5 g ofendo-8-(4-methoxyphenyl)-8-azabicyclo 3.2.1!octan-3-ol.

NMR (ppm, CDCl₃); 1.42-1.49 (1H, m), 1.50-1.57 (1H, m), 1.57-1.66 (1H,m), 2.00-2.11 (2H, m), 2.22-2.43 (4H, m), 3.75 (3H, s), 3.96-4.06 (1H,m), 4.06-4.14 (2H, m), 6.71-6.91 (4H, m).

(3) Endo-8-(4-methoxyphenyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

To a solution of 1.2 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid in 10 ml oftoluene was added 1.5 ml of thionyl chloride. The mixture was stirred at80° C. for an hour. After the solvent was distilled off under vacuum, 10ml of tetrahydrofuran was added to the residue. The solvent was againdistilled off under vacuum.

To the residue was added 10 ml of tetrahydrofuran to give atetrahydrofuran solution of the acid chloride.

Under ice cooling, 2.7 ml of n-butyl lithium (1.56M n-hexane solution)was dropwise added to 10 ml of tetrahydrofuran containing 1 g ofendo-8-(4-methoxyphenyl)-8-azabicyclo 3.2.1!octan-3-ol. The mixture wasstirred for 30 minutes. To the solution was dropwise added thetetrahydrofuran solution of the acid chloride previously prepared.Stirring was continued overnight at room temperature.

After the solvent was distilled off, water was added to the residue,followed by extraction with chloroform. The chloroform layer was driedover anhydrous sodium sulfate. After the solvent was distilled off, theresidue was purified by silica gel column chromatography (chloroform) togive 220 mg of endo-8-(4-methoxyphenyl)-8-azabicyclo 3.2.1!oct-3-yl)1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate.

mp: 136.5°-139° C. (ethyl acetate-isopropyl ether)

Reference Example 2

As a reference example, endo-8-(2-thiazolyl)-8-azabicyclo 3.2.1!oct-3-yl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate hydrochloride(Compound 58) corresponding to the compound of formula (A) wherein X isan oxygen atom, m is 0 and A is 2-thiazolyl was prepared in a mannersimilar to Reference Example 1.

mp: 218.5°-221.5° C. (chloroform-isopropyl ether)

EXAMPLE 8 Preparation of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride

The title compound corresponding to the compound of formula (12),wherein L is chlorine and which is an intermediate for preparing thequinolinecarboxylic acid derivative of the present invention, wasprepared.

A solution of 3.88 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid and 5.0 ml ofthionyl chloride in 50 ml of toluene was stirred at 100° C. for 5 hours.After toluene was distilled off under vacuum, toluene was again added tothe residue. The solvent was again distilled off under vacuum to give4.22 g of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride.

mp: 114°-116° C.

EXAMPLE 9 Preparation of 4-nitrophenyl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

The title compound corresponding to the compound of formula (12),wherein L is 4-nitrophenyloxy and which is an intermediate for preparingthe quinolinecarboxylic acid derivative, was prepared.

To a solution of 1.0 g ofl-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride in 30 ml oftoluene was added 0.55 g of p-nitrophenol. The mixture was stirredovernight at room temperature. After solvent was distilled off, theresidue was extracted with ether. The solvent was again distilled off.The resulting solid was washed with a small quantity of cold ether togive 0.56 g of 4-nitrophenyl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate.

mp: 80°-82° C.

EXAMPLE 10 Endo-3-amino-8-(2-morpholinoethyl)-8-azabicyclo 3.2.1!octanetrihydrochloride

Following the procedures shown in Preparation Scheme V, the titlecompound corresponding to Compound (23) wherein X is imino, q is 2 and Dis morpholino was prepared as an intermediate for producing thequinolinecarboxylic acid derivative.

(1) 8-(2-Morpholinoethyl)-8-azabicyclo 3.2.1!octan-3-one

To a solution of 16.2 ml of 2,5-dimethoxytetrahydrofuran in 50 ml ofwater was added 6 ml of conc. hydrochloric acid. The mixture was stirredat room temperature for 20 minutes. Thereafter, 150 ml of water, 25 mlof 1-(2-aminoethyl)morpholine, 20 ml of conc. hydrochloric acid and 20.1g of 1,3-acetonedicarboxylic acid were successively added to thereaction mixture. Furthermore, a solution of 8.8 g of Na₂ HPO₄ and 2.5 gof sodium hydroxide in 100 ml of water was added to the mixture.Thereafter the pH was adjusted to the range of 2 to 3. After stirringovernight at room temperature, the reaction solution was washed withchloroform. Potassium carbonate was added to the mixture to renderalkaline, followed by extraction with chloroform. The organic layer waswashed with water and then dried over anhydrous sodium sulfate. Thesolvent was then distilled off. The residue was purified by silica gelcolumn chromatography (chloroform:NH₃ -saturated methanol=20:1) to give26.7 g of 8-(2-morpholinoethyl)-8-azabicyclo 3.2.1!octan-3-one.

NMR (ppm, CDCl₃); 1.50-1.77 (3H, m), 1.95-2.10 (2H, m), 2.20 (2H, d,J=15 Hz), 2.40-2.80 (9H, m), 3.50-3.61 (2H, m), 3.68-3.77 (4H, m)

(2) 8-(2-Morpholinoethyl)-8-azabicyclo 3.2.1!octan-3-one oxime

After 22.2 ml of 50% hydroxylamine aqueous solution was added to asolution of 40.0 g of 8-(2-morpholinoethyl)-8-azabicyclo3.2.1!octan-3-one in 200 ml of ethanol, the mixture was stirred at roomtemperature for an hour. The solvent was distilled off and toluene wasadded followed by azeotropic distillation. After the solvent wasdistilled off, the residue was purified by silica gel columnchromatography (chloroform:NH₃ -saturated methanol=20:1) to give 32.8 gof 8-(2-morpholinoethyl)-8-azabicyclo 3.2.1!octan-3-one oxime.

MS (m/z); 253 (M⁺)

NMR (ppm, CDCl₃); 1.40-1.68 (2H, m), 1.80-2.29 (4H, m), 2.40-2.73 (9H,m), 2.95 (1H, d, J=15 Hz), 3.30-3.47 (2H, m), 3.65-3.78 (4H, m), 8.98(1H, brs).

(3) Endo-3-amino-8-(2-morpholinoethyl)-8-azabicyclo 3.2.1!octanetrihydrochloride

To a solution of 15.0 g of 8-(2-morpholinoethyl)-8-azabicyclo3.2.1!octan-3-one oxime in 150 ml of acetic acid was added 1.5 g ofplatinum oxide to perform catalytic hydrogenation under a hydrogenpressure of 5 kg/cm² at 40° C. for 8 hours. After completion of thehydrogenation, insoluble matters were filtered off and 20 ml of conc.hydrochloric acid was added to the filtrate. The mixture wasconcentrated to dryness under vacuum. Recrystallization frommethanol-ethanol gave 5.9 g ofendo-3-amino-8-(2-morpholinoethyl)-8-azabicyclo 3.2.1!octanetrihydrochloride.

mp: >213° C. (decompd.)

NMR (ppm, CDCl₃) (free); 1.00-1.50 (4H, m), 1.88-2.20 (6H, m), 2.40-2.55(8H, m), 3.13-3.27 (3H, m), 3.65-3.78 (4H, m)

EXAMPLE 11 Preparation of endo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo3.2.1!octane

Following the procedures shown in Preparation Scheme V, the titlecompound corresponding to Compound (23) wherein X is imino, q is 2 and Dis hydroxymethyl was prepared as an intermediate for producing thequinolinecarboxylic acid derivative.

1) 8-(3-Hydroxypropyl)-8-azabicyclo 3.2.1!octan-3-one

In a nitrogen flow, 45 ml of conc. hydrochloric acid was added to asolution of 120 ml of 2,5-dimethoxytetrahydrofuran in 300 ml of waterwhile stirring at room temperature. Twenty minutes after, the reactionsolution became homogenous. Thereafter, 450 ml of water, a solution of105 ml of 3-amino-1-propanol and 138 ml of conc. hydrochloric acid in600 ml of water, a solution of 150 g of 1,3-diacetonedicarboxylic acidin 700 ml of water and a solution of 66 g of Na₂ HPO₄ in 300 ml of waterwere successively added to the homogenous reaction solution.Furthermore, about 215 ml of 40% sodium hydroxide aqueous solution wasadded to the mixture. The pH of the resulting solution was then adjustedto the range of 3 to 4. After bubbling was confirmed, the mixture wasstirred overnight. Then conc. hydrochloric acid was added to adjust thepH of the reaction solution to 3. The reaction solution was heated to80° C. and stirred until bubbling of carbon dioxide gas was notobserved. After completion of the reaction, the reaction solution wascooled and sodium hydroxide aqueous solution was added thereto to renderalkaline. Thereafter sodium chloride was added for salting out, followedby extraction with chloroform. The chloroform layer was washed withwater and then dried over anhydrous sodium sulfate. The solvent wasdistilled off to give 8-(3-hydroxypropyl)-8-azabicyclo 3.2.1!octan-3-oneas the crude product.

NMR (ppm, CDCl₃); 1.58-1.69 (2H, m), 1.71-1.86 (2H, m), 2.00-2.30 (4H,m), 2.59-2.72 (2H, m), 2.81 (2H, t, J=5.9 Hz), 3.58-3.70 (2H, m), 3.88(2H, t, J=5.3 Hz), 5.10 (1H, brs)

(2) 8-(3-Hydroxypropyl)-8-azabicyclo 3.2.1!octan-3-one oximehydrochloride

The crude product of 8-(3-hydroxypropyl)-8-azabicyclo 3.2.1!octan-3-onewas dissolved in 1200 ml of ethanol and 72.9 g of 50% hydroxylamineaqueous solution was added to the solution at room temperature, whilestirring. After completion of the reaction, the solvent was distilledoff and toluene was added. The solvent was again distilled off andethanol was added to the residue. An equimolar volume of conc.hydrochloric acid was then added to the mixture. The precipitatedcrystals were filtered to give 161 g of8-(3-hydroxy-propyl)-8-azabicyclo 3.2.1!octan-3-one oxime hydrochloride.

NMR (ppm, methanol-d₄); 1.75-2.08 (4H, m), 2.21-2.56 (4H, m), 2.83-2.93(1H, m), 3.19-3.45 (3H, m), 3.73 (2H, t, J=5.7 Hz), 4.14-4.20 (2H, m)

(3) Endo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo 3.2.1!octane

A solution of 100 g of 8-(3-hydroxypropyl)-8-azabicyclo3.2.1!octan-3-one oxime hydrochloride and 5 g of platinum oxide in 500ml of acetic acid was reacted for about 18 hours under a hydrogenpressure of 5.0-5.4 kg/cm², while maintaining at 45° to 46° C. Afteradding water, the reaction mixture was filtered and the filtrate wasconcentrated. After 50 ml of water and 100 ml of methanol were added tothe concentrate, a solution of 38.4 g of oxalic acid in 200 ml ofmethanol was added thereto and further 200 ml of methanol was added tothe mixture, followed by stirring overnight at room temperature. Theprecipitated crystals were filtered and dried to give 71.3 g ofendo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo 3.2.1!octane hydrochlorideoxalate.

mp: 175°-185° C. (decompd.)

In 300 ml of water was dissolved 30.0 g ofendo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo 3.2.1!octane hydrochlorideoxalate, and 48.3 g of potassium hydrogencarbonate was then dissolved inthe solution. The mixture was stirred at room temperature for 4 hours.Furthermore 300 ml of ethanol was added thereto. After stirring for anhour, precipitated insoluble matters were filtered off and the filtratewas concentrated. Again 300 ml of ethanol was added to the concentrate.The precipitated insoluble matters were filtered off and the filtratewas concentrated. The concentrate was dissolved in 300 ml of chloroform.After drying over anhydrous sodium sulfate, the solvent was distilledoff to give endo-3-amino-8-(3-hydroxy-propyl)-8-azabicyclo 3.2.1!octane.

NMR (ppm, CDCl₃); 1.43-1.50 (2H, m), 1.54-1.71 (2H, m), 1.85-2.14 (6H,m), 2.60 (2H, t, J=5.6 Hz), 3.19-3.37 (3H, m), 3.85 (2H, t, J=5.2 Hz)

EXAMPLE 12 Preparation of endo-3-amino-8-(2-ethoxyethyl)-8-azabicyclo3.2.1!octane

The title compound corresponding to Compound (23) wherein X is imino, qis 2 and D is ethoxy was prepared in a manner similar to Example 11, asan intermediate for producing the quinolinecarboxylic acid derivative.

1) 8-(2-Ethoxyethyl)-8-azabicyclo 3.2.1!octan-3-one

NMR (ppm, CDCl₃); 1.22 (3H, t, J=7.0 Hz), 1.53-1.64 (2H, m), 1.90-2.23(4H, m), 2.65-2.75 (2H, m), 2.82 (2H, t, J=6.0 Hz), 3.45-3.71 (6H, m) 2)8-(2-Ethoxyethyl)-8-azabicyclo 3.2.1!octan-3-one oxime

MS (m/z); 212 (M⁺), 153

NMR (ppm, CDCl₃); 1.21 (3H, t, J=7.0 Hz), 1.42-1.69 (2H, m), 1.86-2.28(4H, m), 2.59 (1H, dd, J=14.9, 3.3 Hz), 2.71 (2H, t, J=6.3 Hz), 2.95(1H, d, J=15.6 Hz), 3.42-3.63 (6H, m), 8.68 (1H, brs)

3) Endo-3-amino-8-(2-ethoxyethyl)-8-azabicyclo 3.2.1!octane

MS (m/z); 198 (M⁺), 82

NMR (ppm, CDCl₃); 1.20 (3H, t, J=7.0 Hz), 1.31-1.69 (4H, m), 1.84-2.00(4H, m), 2.00-2.23 (2H, m), 2.57 (2H, t, J=6.7 Hz), 3.19-3.25 (3H, m),3.45-4.01 (4H, m)

EXAMPLE 13 Preparation of endo-N-(8-(3-hydroxypropyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 5)

Following the procedures shown in Preparation Scheme IV, the titlecompound corresponding to Compound (17) wherein X is imino, q is 2 and Dis hydroxymethyl was prepared.

1) 2-Isopropylaminobenzyl alcohol

While maintaining at 0° to 5° C., a solution of 140 g of sodiumborohydride in 500 ml of 0.5% sodium hydroxide aqueous solution wasdropwise added over 2 hours to a solution mixture of 150 g of2-aminobenzyl alcohol, 300 g of sodium acetate trihydrate, 850 ml ofacetic acid, 950 ml of water, 275 ml of ethanol and 500 ml of acetone.Stirring was continued at the same temperature for an hour. Thereafterthe reaction mixture was neutralized with potassium carbonate, followedby extraction with hexane. The organic layer was washed with water andthen with saturated sodium chloride aqueous solution. The solvent wasdistilled off under vacuum. Distillation under vacuum gave 142 g of2-isopropylaminobenzyl alcohol.

bp: 110°-114° C. (4 mmHg)

2) 2-Isopropylaminobenzaldehyde

While heating a solution of 40 g of 2-isopropylaminobenzyl alcohol in200 ml toluene at 100° C., 58 g in total of activated manganese dioxidewas added several times to the solution. After stirring at the sametemperature for 30 minutes, insoluble matters were filtered off. Thesolvent was distilled off to give 2-isopropylaminobenzaldehyde.

NMR (ppm, CDCl₃); 1.27 (6H, d, J=6.4 Hz), 3.67-3.83 (1H, m), 6.59-6.73(2H, m), 7.31-7.43 (1H, m), 7.44 (1H, dd, J=7.6, 1.4 Hz), 8.26 (1H, s),9.79 (1H, s)

The thus obtained 2-isopropylaminobenzaldehyde was dissolved in tolueneand 4N hydrochloric acid ethyl acetate solution was added thereto underice cooling. Thus, 42.6 g of 2-isopropylaminobenzaldehyde hydrochloridewas obtained.

3-1) Ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

A solution of 133.7 g of 2-isopropylaminobenzaldehyde hydrochloride, 200g of diethyl malonate, 70 ml of piperidine, 70 ml of acetic acid, 50 gof potassium carbonate and 1.5 liter of toluene was heated to reflux for10 hours. The reaction solution was washed with water and then withsaturated sodium hydrogencarbonate aqueous solution, and dried overanhydrous magnesium sulfate. The solvent was distilled off to give 256 gof ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate as thecrude product.

3-2) Ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

A solution of 20.0 g of 2-isopropylaminobenzaldehyde, 29.4 g of diethylmalonate, 10 ml of piperidine, 10 ml of acetic acid and 500 ml oftoluene was heated to reflux for 13 hours. The reaction solution waswashed with water and then with saturated sodium hydrogencarbonateaqueous solution, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off to give 52 g of ethyl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate as the crudeproduct.

4-1) 1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid

While stirring a solution of 256 g of the crude ethyl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate in 200 ml ofethanol under ice cooling, 500 ml of an aqueous solution of 52 g ofsodium hydroxide was added to the solution. The mixture was stirred atroom temperature for 2 hours.

The reaction solution was washed with toluene and conc. hydrochloricacid was then added to render the system acidic. The precipitates werefiltered, washed with water and dried to give 126.7 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid.

4-2) 1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid

A solution of 5.0 g of 2-isopropylaminobenzaldehyde, 4.8 g of malonicacid, 5 ml of piperidine, 5 ml of acetic acid and 50 ml of toluene washeated to reflux for 3.5 hours. The reaction solution was washed withwater. The crude product partly precipitated was filtered. The filtratewas extracted with 2N sodium hydroxide aqueous solution and theprecipitates above was dissolved in the extract. The resulting solutionwas washed with toluene and aqueous hydrochloric acid solution was thenadded thereto to render the system acidic. The precipitates were washedwith water and dried to give 3.9 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid.

5) 1-Isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride

A solution of 3.88 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid and 5.0 ml ofthionyl chloride in 50 ml of toluene was stirred at 100° C. for 5 hours.After toluene was distilled off under vacuum, toluene was again added tothe residue. The solvent was again distilled off under vacuum to give4.22 g of 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride.

mp: 114°-116° C.

6-1) Endo-N-(8-(3-hydroxypropyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide

In 150 ml of toluene was dissolved 18.7 g ofendo-3-amino-8-(3-hydroxypropyl)-8-azabicyclo 3.2.1!octane. Whilestirring at room temperature, a solution of 24.1 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride in 200 ml oftoluene was dropwise added to the above solution. Stirring was continuedfor an hour. The reaction solution was concentrated. Thereafter 150 mlof methanol and 50 ml of 20% sodium hydroxide aqueous solution wereadded to the concentrate. The mixture was stirred at room temperaturefor 30 minutes. The solvent was distilled off and water was added to theresidue, followed by extraction with chloroform.

The chloroform layer was washed with water and dried over anhydroussodium sulfate. The solvent was distilled off and the residue wasrecrystallized from ethanol-ethyl acetate to give 22.9 g ofendo-N-(8-(3-hydroxypropyl)-8-azabicyclo(3.2.1oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

6-2) Endo-N-(8-(3-hydroxypropyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide

In 50 ml of toluene was suspended 5.0 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid. After 7.7 mlof thionyl chloride was added to the suspension, the mixture was heatedat 80° C. for an hour with stirring. After completion of the reaction,the solvent was distilled off. Again 50 ml of toluene was added todissolve the residue. The solvent was distilled off to give the acidchloride.

In 40 ml of water was dissolved 6.71 g ofendo-N-(8-(3-hydroxypropyl)-8-azabicyclo 3.2.1!octane hydrochlorideoxalate. After a solution of 4.85 g of potassium hydroxide in 40 ml ofwater was added to the solution above, the mixture was stirred at roomtemperature for 20 minutes. After 70 ml of tetrahydrofuran was addedthereto, a solution obtained by dissolving the acid chloride previouslyobtained in 50 ml of toluene was dropwise added to the mixture. Stirringwas continued for 30 minutes. The reaction solution was concentrated.Thereafter 150 ml of methanol and 50 ml of 20% potassium hydroxideaqueous solution were added to the concentrate. The resulting mixturewas stirred at room temperature for 30 minutes. The reaction solutionwas concentrated and water was added to the concentrate. The mixture wasthen extracted with chloroform. After washing with water, the extractwas dried over anhydrous sodium sulfate. The solvent was distilled offand the residue was recrystallized from ethanol-ethyl acetate to give6.5 g of endo-N-(8-(3-hydroxypropyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

mp: 167°-169° C. (ethanol-isopropyl ether)

MS (m/z); 397 (M⁺), 128

NMR (ppm, CDCl₃); 1.68 (6H, d, J=8 Hz), 1.62-1.78 (2H, m), 1.80-1.96(2H, m), 2.00-2.38 (6H, m), 2.72 (2H, t, J=6 Hz), 3.42 (2H, brs), 3.88(2H, t, J=6 Hz), 4.30 (1H, q, J=7 Hz), 5.45-5.80 (1H, brs), 7.23-7.33(1H, m), 7.56-7.70 (2H, m), 7.75 (1H, d, J=7 Hz), 8.83 (1H, s), 10.51(1H, d, J=8 Hz)

EXAMPLE 14 Preparation of endo-N-(8-(2-morpholinoethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 20)

Following the procedures shown in Preparation Scheme IV, the titlecompound corresponding to Compound (17) wherein X is imino, q is 2 and Dis morpholino was prepared.

In 50 ml of toluene was suspended 1.03 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid. After 5.0 mlof thionyl chloride was added to the suspension, the mixture was heatedat 100° C. for 3 hours with stirring. After completion of the reaction,the solvent was distilled off. Again 20 ml of toluene was added todissolve the residue. The solvent was distilled off to give the acidchloride.

A solution of 3.2 g of endo-3-amino-8-(2-morpholinoethyl)-8-azabicyclo3.2.1!octane in 50 ml of tetrahydrofuran was dropwise added to the acidchloride under ice cooling. The mixture was stirred at room temperaturefor an hour. The reaction solution was diluted with ethyl acetate andthen washed successively with saturated sodium hydrogencarbonate andwith saturated sodium chloride aqueous solution. After drying overanhydrous sodium sulfate, the solvent was distilled off and the residuewas recrystallized from ethyl acetate to give 1.7 g ofendo-N-(8-(2-morpholinoethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

mp: 178°-180° C. (ethanol-ethyl acetate)

NMR (ppm, CDCl₃); 1.67-1.80 (8H, m), 2.05-2.31 (6H, m), 2.49-2.58 (8H,m), 3.27 (2H, brs), 3.70-3.74 (4H, m), 4.28 (1H, q, J=7.3 Hz), 5.60 (1H,brs), 7.25-7.32 (1H, m), 7.61-7.64 (2H, m), 7.75 (1H, d, J=7.7 Hz), 8.83(1H, s), 10.48 (1H, d, J=7.8 Hz)

Reference Example 3 Endo-N-(8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide

The title compound corresponding to Compound (8), wherein X is imino andwhich is an intermediate for preparing the quinolinecarboxylic acidderivative, was prepared according to Preparation Scheme III.

Several drops of trifluoroacetic acid was added to a solution of 1.0 gof endo-N-(8-((1,1-dimethylethoxy)carbonyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide in10 ml of methylene chloride. After stirring at room temperature for 30minutes, the reaction mixture was washed with saturated sodiumbicarbonate aqueous solution and dried over anhydrous sodium sulfate.

The solvent was distilled off and the residue was recrystallized fromethyl acetate to give 0.58 g of endo-N-(8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

mp: 205°-207° C. (ethyl acetate)

MS (m/z); 339 (M⁺), 214

NMR (ppm, CDCl₃); 1.70 (6H, d, J=7.0 Hz), 1.91-2.48 (8H, m), 3.81 (2H,brs), 4.40 (1H, q, J=6.9 Hz), 5.60 (1H, brs), 7.24-7.33 (1H, m),7.61-7.68 (2H, m), 7.75 (1H, d, J=7.0 Hz), 8.84 (1H, s), 10.60 (1H, d,J=7.0 Hz)

Reference Example 4 Preparation ofendo-3-amino-8-(2,2,2-trifluoroethyl)-8-azabicyclo 3.2.1!octanedihydrochloride

The title compound corresponding to Compound (23), wherein X is imino, qis 1 and D is trifluoromethyl, was prepared as the intermediateaccording to Preparation Scheme V.

1) 8-(2,2,2-Trifluoroethyl)-8-azabicyclo 3.2.1!octan-3-one

MS (m/z); 207, 150

NMR (ppm, CDCl₃); 1.66 (2H, d, J=7.8 Hz), 1.95-2.15 (2H, m), 2.24 (2H,dd, J=17.2, 1.6 Hz), 2.68 (2H, dd, J=16.4, 4.6 Hz), 3.15 (2H, q, J=9.2Hz), 3.50-3.70 (2H, m)

2) 8-(2,2,2-Trifluoroethyl)-8-azabicyclo 3.2.1!octan-3-one oxime

MS (m/z); 222, 205

NMR (ppm, CDCl₃); 1.50-1.80 (2H, m), 1.80-2.05 (2H, m), 2.10-2.30 (2H,m), 2.57 (1H, dd, J=15.2, 3.6 Hz), 3.00-3.10 (1H, m), 3.00 (2H, q, J=9.2Hz), 3.35-3.50 (2H, m)

3) Endo-3-amino-8-(2,2,2-trifluoroethyl)-8-azabicyclo 3.2.1!octanedihydrochloride

MS (m/z); 208 (M⁺), 150

NMR (ppm, DMSO-d₆); 1.87 (1H, s), 1.95 (1H, s), 2.00-2.38 (4H, m),2.38-2.78 (2H, m), 3.25-3.50 (1H, m), 3.50-4.30 (4H, m), 8.42 (3H, brs)

Reference Example 5 Preparation ofendo-3-amino-8-(5-acetyloxypentyl)-8-azabicyclo 3.2.1!octane

The title compound corresponding to Compound (23), wherein X is imino, qis 5 and D is acetyloxy, was prepared as the intermediate according toPreparation Scheme V.

1) 8-(5-Hydroxypentyl)-8-azabicyclo 3.2.1!octan-3-one

MS (m/z); 211 (M⁺), 154, 138

NMR (ppm, CDCl₃); 1.31-1.82 (8H, m), 1.83-2.12 (3H, m), 2.52-2.77 (4H,m), 2.19 (2H, dd, J=17.0, 2.0 Hz), 3.67 (2H, t, J=6.5 Hz), 3.46-3.60(2H, m)

2) 8-(5-Hydroxypentyl)-8-azabicyclo 3.2.1!octan-3-one oxime

MS (m/z); 226 (M⁺), 154

NMR (ppm, CDCl₃); 1.30-1.75 (9H, m), 1.75-2.05 (2H, m), 2.10 (1H, d,J=15.4 Hz), 2.15-2.27 (1H, m), 2.49 (2H, t, J=6.6 Hz), 2.45-2.65 (1H,m), 2.96 (1H, d, J=15.4 Hz), 3.25-3.45 (2H, m), 3.65 (2H, t, J=6.2 Hz),7.85-8.06 (1H, brs)

3) Endo-3-amino-8-(5-acetyloxypentyl)-8-azabicyclo 3.2.1!octanedihydrochloride

NMR (ppm, DMSO-d₆); 1.22-1.50 (2H, m), 1.50-1.88 (4H, m), 1.99 (3H, s),2.05-2.30 (4H, m), 2.60-2.96 (4H, m), 3.02-3.18 (1H, m), 3.25-3.61 (3H,m), 3.88-3.99 (2H, m), 4.00 (2H, t, J=7.0 Hz), 8.42 (3H, br), 10.80 (1H,brs)

Reference Example 6 Preparation ofendo-3-amino-8-(2-(N,N-diethylamino)ethyl)-8-azabicyclo 3.2.1!octanetrihydrochloride

The title compound corresponding to Compound (23), wherein X is imino, qis 2 and D is diethylamino, was prepared as the intermediate accordingto Preparation Scheme V.

1) 8-(2-(N,N-Diethylamino)ethyl)-8-azabicyclo 3.2.1!octan-3-one

MS (m/z); 224 (M⁺), 86

NMR (ppm, CDCl₃); 1.05 (6H, t, J=7.2 Hz), 1.59 (2H, d, J=7.8 Hz), 2.15(1H, s), 2.45-2.85 (13H, m), 3.50-3.70 (2H, m)

2) 8-(2-(N,N-Diethylamino)ethyl)-8-azabicyclo 3.2.1!octan-3-one oxime

MS (m/z); 239 (M⁺), 86

NMR (ppm, CDCl₃); 1.08 (6H, t, J=7.2 Hz), 1.45-1.70 (2H, m), 1.85-2.30(5H, m), 2.50-2.75 (8H, m), 2.96 (1H, d, J=15.6 Hz), 3.33-3.50 (2H, m)

3) Endo-3-amino-8-(2-(N,N-diethylamino)ethyl)-8-azabicyclo 3.2.1!octanetrihydrochloride

MS (m/z); 225 (M⁺), 82

NMR (ppm, DMSO-d₆); 1.26 (6H, t, J=7.2 Hz), 2.00-2.40 (5H, m), 2.60-2.90(2H, m), 2.90-3.28 (4H, m), 3.28-3.80 (6H, m), 3.85-4.20 (2H, m), 8.51(3H, brs), 11.10-11.35 (1H, brs), 11.35-11.80 (1H, brs)

Reference Example 7 Preparation ofendo-8-(2,2,2-trifluoroethyl)-8-azabicyclo 3.2.1!octan-3-ol

The title compound corresponding to Compound (23), wherein X is oxygen,q is 1 and D is trifluoromethyl, was prepared as the intermediateaccording to Preparation Scheme V. Specifically, the title compound canbe prepared according to Reference Example 1 (1) and (2).

MS (m/z): 209 (M⁺), 192, 164, 150

Reference Example 8 Preparation of ethylendo-N-(8-(2-ethoxyethyl)-8-azabicyclo 3.2.1!oct-3-yl)carbamoylacetate

The title compound corresponding to Compound (22), wherein X is imino, qis 2 and D is ethoxy, was prepared as the intermediate according toPreparation Scheme VI.

A solution of 16.44 g of endo-3-amino-8-(2-ethoxyethyl)-8-azabicyclo3.2.1!octane and 63 ml of diethyl malonate in 150 ml of toluene wasreacted for 3 hours under reflux with heating. After completion of thereaction, the reaction mixture was extracted with 10% aqueoushydrochloric acid solution. Potassium carbonate was added to the aqueouslayer to render alkaline, followed by extraction with chloroform. Thechloroform layer was washed and dried over anhydrous sodium sulfate. Thesolvent was distilled off and the residue was purified by silica gelcolumn chromatography (chloroform:NH3-saturated methanol=50:1) to give20.7 g of ethyl endo-N-(8-(2-ethoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)carbamoylacetate.

NMR (ppm, CDCl₃); 1.20 (3H, t, J=7.0 Hz), 1.30 (3H, t, J=7.2 Hz),1.55-2.27 (8H, m), 2.57 (2H, t, J=6.4 Hz), 3.19-3.29 (4H, m), 3.45-3.57(4H, m), 4.06-4.27 (3H, m), 7.92 (1H, d, J=3.5 Hz)

Reference Example 9 Preparation of ethylendo-N-(8-(2-morpholinoethyl)-8-azabicyclo3.2.1!oct-3-yl)carbamoylacetate

The title compound corresponding to Compound (22), wherein X is imino, qis 2 and D is morpholino, was prepared in a manner similar to ReferenceExample 4, as the intermediate.

MS (m/z); 353 (M⁺), 253

NMR (ppm, CDCl₃); 1.30 (3H, t, J=7.0 Hz), 1.51-1.68 (2H, m), 1.68-1.91(3H, m), 2.00-2.24 (4H, m), 2.34-2.62 (7H, m), 3.17-3.32 (4H, m),3.64-3.75 (4H, m), 4.12 (1H, q, J=7.5 Hz), 4.23 (2H, q, J=7.0 Hz),7.87-8.01 (1H, br)

EXAMPLE 15 Preparation of endo-N-(8-(2-ethoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide(Compound 11)

The title compound corresponding to Compound (17), wherein X is imino, qis 2 and D is ethoxy, was prepared according to Preparation Scheme VI.

A solution of 40.97 g of ethyl endo-N-(8-(2-ethoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)carbamoylacetate, 25.96 g of 2-isopropylaminobenzaldehydehydrochloride, 19.28 ml of piperidine, 18.60 ml of acetic acid and 21.56g of potassium carbonate in 600 ml of toluene was heated for 5 hourswith stirring. After completion of the reaction, the reaction mixturewas washed with water. The organic layer was dried over anhydrous sodiumsulfate. The solvent was distilled off and the residue was purified bysilica gel column chromatography (chloroform:NH₃ -saturatedmethanol=50:1) to give 28.31 g of endo-N-(8-(2-ethoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

Reference Example 10

The following compounds are prepared in a manner similar to ReferenceExample 4.

1) Ethyl endo-N-(8-(3-hydroxypropyl)-8-azabicyclo3.2.1!oct-3-yl)carbamoylacetate

2) Ethyl endo-N-(8-(2-methoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)carbamoylacetate

3) Ethyl endo-(8-(2-morpholinoethyl)-8-azabicyclo3.2.1!oct-3-yl)oxycarbonylacetate

4) Ethyl endo-(8-(3-hydroxypropyl)-8-azabicyclo3.2.1!oct-3-yl)oxycarbonylacetate

5) Ethyl endo-(8-(2-methoxyethyl)-8-azabicyclo3.2.1!oct-3-yl)oxycarbonylacetate

Reference Example 11 Preparation of endo-(8-methyl-8-azabicyclo3.2.1!oct-3-yl) 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

The title compound corresponding to Compound (7), wherein X is oxygen,was prepared as the intermediate according to Preparation Scheme I.

1) Ethyl 2-oxo-1,2-dihydro-3-quinolinecarboxylate

In 700 ml of acetic acid was dissolved 45 g of diethyl2-nitrobenzylidenemalonate (J. Org. Chem., 3462, 1960). Whilemaintaining at 80° C., 53 g in total of iron powders were added severaltimes to the solution. Stirring was continued for further 2 hours.

After the temperature was then reverted to room temperature, thereaction mixture was filtered through Celite and the filtrate wasconcentrated under vacuum. The resulting oily substance was purifiedfrom silica gel column chromatography (chloroform:methanol=10:1) to give21.3 g of ethyl 2-oxo-1,2-dihydro-3-quinolinecarboxylate.

mp: 160°-163.2° C. (ethyl acetate)

2) Ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

After 20 g of ethyl 2-oxo-1,2-dihydro-3-quinolinecarboxylate was addedto a solution of 4.45 g of sodium hydride in 100 ml ofdimethylformamide, 31.5 g of isopropyl iodide was added to the mixture,followed by stirring at 70° C. for 8 hours. DMF was distilled off undervacuum. The residue was then poured onto water followed by extractionwith ethyl acetate. The organic layer was washed with water and thenwith saturated sodium chloride aqueous solution and dried over anhydroussodium sulfate.

The solvent was distilled off under vacuum. The resulting oily substancewas purified by silica gel column chromatography (ethylacetate:n-hexane=4:1) to give 1.55 g of ethyl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate.

mp: 54°-57° C. (ethyl acetate)

3) 1-Isopropyl-2-oxo-1,2-dihydro-3-quinoline-carboxylic acid

A solution of 1.55 g of ethyl1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate and 0.28 g ofsodium hydroxide in 10 ml of ethanol and 2 ml of water was stirredovernight at room temperature. The solvent was distilled off and dil.hydrochloric acid was added to the residue. The precipitated solid wasfiltered, washed with water and dried to give 0.24 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid.

mp: 168°-169° C. (ethyl acetate)

4) Endo-(8-methyl-8-azabicyclo 3.2.1!oct-3-yl)1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate

To a suspension of 1 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid in 10 ml oftetrahydrofuran was added 1.6 ml of thionyl chloride. The mixture wasstirred at 80° C. for an hour. After the solvent was distilled off undervacuum, 10 ml of tetrahydrofuran was added to the residue. The solventwas again distilled off under vacuum and 20 ml of tetrahydrofuran wasadded to the residue to form a tetrahydrofuran solution of the acidchloride.

Under ice cooling, 3.5 ml of n-butyl lithium (1.56M n-hexane solution)was dropwise added to a solution of 740 mg of tropine in 10 ml oftetrahydrofuran. The mixture was stirred for 30 minutes. Thetetrahydrofuran solution of the acid chloride previously prepared wasdropwise added to the solution. Stirring was continued overnight at roomtemperature. The solvent was distilled off and 2N hydrochloric acid wasadded thereto. After washing with ethyl acetate, the aqueous layer wasrendered basic with sodium hydrogencarbonate. Thereafter the mixture wasextracted with chloroform. The chloroform layer was dried over anhydroussodium sulfate. The solvent was distilled off and the residue waspurified by silica gel column chromatography (chloroform:methanol=20:1)to give 530 mg of endo-(8-methyl-8-azabicyclo 3.2.1!oct-3-yl)1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate.

MS (m/z); 354 (M⁺), 310, 269, 172, 124

IR ν (cm⁻¹, Neat); 2937, 1733, 1652, 1211, 1034, 754.

NMR (ppm, CDCl₃);

1.66 (6H, d, J=6.9 Hz), 1.88 (1H, s), 1.92 (1H, s), 2.00-2.30 (6H, m),2.32 (3H, s), 3.17 (2H, s), 5.27 (1H, t, J=5.4 Hz), 5.30-5.70 (1H, brs),7.19-7.30 (1H, m), 7.55-7.68 (3H, m), 8.22 (1H, s).

Reference Example 12 Preparation of endo-N-(8-methyl-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide

The title compound corresponding to Compound (7), wherein X is imino,was prepared as the intermediate according to Preparation Scheme I.

A solution of 0.5 g of1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid in 5 ml ofthionyl chloride was stirred to reflux for 2 hours. After thionylchloride was thoroughly distilled off under vacuum, 3 ml of benzene wasadded to the residue. Under ice cooling a solution of 0.36 g ofendo-3-amino-8-methyl-8-azabicyclo 3.2.1!octane in 3 ml of benzene wasdropwise added to the benzene solution of the acid chloride describedabove. The mixture was stirred at room temperature for 2 hours. Afterethyl acetate was added thereto, the organic layer was washed with waterand then with saturated sodium bicarbonate aqueous solution and driedover anhydrous magnesium sulfate. The solvent was distilled off undervacuum. The resulting residue was purified by alumina columnchromatography (chloroform) to give 390 mg ofendo-N-(8-methyl-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.

mp: 175.8°-177.8° C. (ethyl acetate)

MS (m/z); 353 (M⁺), 214, 172, 84.

IR ν (cm⁻¹, Neat); 3263, 1673, 1528, 1206.

NMR (ppm, CDCl₃); 1.68 (6H, d, J=7.2 Hz), 1.76 (1H, s), 1.83 (1H, s),2.00-2.40 (6H, m), 2.34 (3H, s), 3.10-3.28 (2H, m), 4.30 (1H, q, J=7.2Hz), 5.40-5.90 (1H, m), 7.22-7.33 (1H, m), 7.55-7.70 (2H, m), 7.75 (1H,d, J=7.8 Hz), 8.83 (1H, s), 10.48 (1H, d, J=7.2 Hz).

Experiments

The numbering of the compounds used in Experiments 1 through 4corresponds to the numbering of those shown in Examples. Table 1 showsthe relationship in numbering.

                  TABLE 1                                                         ______________________________________                                         ##STR15##                                                                    Compound     X      m        A                                                ______________________________________                                         1           NH     1        CHCH.sub.2                                        2           NH     1        CCH                                               3           NH     1        CF.sub.3                                          4           NH     2        OH                                                5           NH     3        OH                                                6           NH     4        OH                                                7           NH     5        OH                                                8           NH     6        OH                                                9           NH     5        OAc                                              10           NH     2        OMe                                              11           NH     2        OEt                                              14           NH     2        O(CH.sub.2).sub.2 OMe                            16           NH     2        NEt.sub.2                                        17           NH     2        SMe                                              18           NH     2        SOMe                                             19           NH     2        SO.sub.2 Ph                                      20           NH     2                                                                                       ##STR16##                                       21           NH     2                                                                                       ##STR17##                                       22           NH     1                                                                                       ##STR18##                                       23           NH     2                                                                                       ##STR19##                                       24           NH     0        CO.sub.2 -t-Bu                                   25           NH     1        CO.sub.2 Et                                      26           NH     1        CO.sub.2 H                                       27           NH     3        CO.sub.2 Et                                      28           NH     3        CO.sub.2 H                                       29           NH     0        COMe                                             30           NH     1        COMe                                             31           NH     3        COMe                                             32           NH     1        CN                                               33           NH     2        CN                                               34           NH     1        CONH.sub.2                                       35           O      1        CHCH.sub.2                                       36           O      1        CCH                                              37           O      2        OH                                               38           O      3        OH                                               39           O      4        OH                                               40           O      5        OH                                               41           O      6        OH                                               42           O      2        OMe                                              43           O      2        OEt                                              44           O      2        NEt.sub.2                                        45           O      2        SMe                                              46           O      2        SO.sub.2 Ph                                      47           O      2                                                                                       ##STR20##                                       48           O      1                                                                                       ##STR21##                                       49           O      2                                                                                       ##STR22##                                       50           O      1        CO.sub.2 Et                                      51           O      3        CO.sub.2 Et                                      52           O      1        COMe                                             53           O      3        COMe                                             54           O      1        CN                                               55           O      2        CN                                               56           O      1        CONH.sub.2                                       57 (Comparison)                                                                            O      0                                                                                       ##STR23##                                       58 (Comparison)                                                                            O      0                                                                                       ##STR24##                                       59           O      2        O(CH.sub.2).sub.2 OMe                            ______________________________________                                    

Experiment 1

Stimulating activity on serotonin 4 receptor

Stimulating activity on serotonin 4 receptor (5-HT₄) of thequinolinecarboxylic acid derivative of the present invention wasexamined by measuring twitch responses in guinea pig ileum, according tothe method described in Craig, D. A. and Clarke D. E., The Journal ofPharmacology and Experimental Therapeutics, 252, 1378-1386, 1990:"Pharmacological characterization of a neuronal receptor for5-hydroxytryptamine in guinea pig ileum with properties similar to the5-hydroxytryptamine 4 receptor".

1) Method

From Harley guinea pigs weighing 250 to 400 g, a section of ileum 10 to20 cm proximal to the ileocecal junction was removed. Longitudinalmuscle strips obtained from the ileum were used for this assay. Thepreparations were suspended in Krebs' solution at 32 to 34° C., bubbledcontinuously with 95% O₂ and 5% CO₂, and subjected to initial tension ofabout 0.8 g. Responses were recorded isometrically. Twitch responseswere evoked by electrical stimulation (0.2 Hz, 1 msec pulse duration).The preparations were stimulated at supramaximal voltage for 2 to 3hours, and were then allowed to equilibrate for about 1 hour atsubmaximal voltage. After it was confirmed that the twitch responseswere enhanced by 10⁻⁸ M serotonin, each agonist was examined on itsactivity for twitch responses. The preparations were left for at least45 minutes before cumulative addition of each agonist.

The quinolinecarboxylic acid derivatives of the present invention wereemployed as sample compounds. For comparison, the following compoundswere employed. These compounds were diluted by dissolving them indistilled water or in DMSO. Each sample compound and cisapride wereprepared in such a manner that the concentration of DMSO in Bath is 0.3%or less.

Comparative Compound 1: Cisapride ##STR25## Comparative Compound 2:compound claimed in U.S. Pat. No. 5,106,851 ##STR26## ComparativeCompound 3: compound specifically disclosed in U.S. Pat. No. 5,106,851##STR27## Comparative Compound 4: compound specifically disclosed inEuropean Patent Application No. 0458636Al ##STR28## 2) Results

The ED₅₀ value of the stimulating activity on serotonin 4 receptor,which is the concentration of the activity for enhancing the twitchresponse by 50%, when the maximum contraction of a sample compound ismade 100%, was determined. The data obtained was analyzed by RS1 (BBNSoftware Product Co.).

The results are shown in Table 2 below.

                  Table 2                                                         ______________________________________                                        Stimulating activity on 5-HT.sub.4 receptor (twitch                           response in guinea pig ileum)                                                 Compound  ED.sub.50 (nM)                                                                           Compound    ED.sub.50 (nM)                               ______________________________________                                         1        59.2       37          16.1                                          4        45.9       38          11.9                                          5        32.0       39          16.6                                          6        38.5       40          25.5                                          7        30.8       41          50.9                                          8        62.3       42          18.4                                          9        33.0       43          15.2                                         10        15.0       44          72.6                                         11        18.7       45          29.5                                         17        48.0       46          46.5                                         19        86.6       47          30.8                                         20        25.5       48          55.9                                         22        24.0       49          39.0                                         26        66.1       51          23.0                                         27        19.3       52          24.6                                         28        91.4       53          26.4                                         30        11.5       55          27.3                                         31        52.3       56          31.4                                         33        35.8       57 (comparison)                                                                           >3000                                        34        61.9       58 (comparison)                                                                            1140                                        35        54.4       59          73.7                                                              Comparative 271.3                                                             Compound 1                                                                    Comparative >3000                                                             Compound 2                                                                    Comparative >3000                                                             Compound 3                                                                    Comparative >3000                                                             Compound 4                                               ______________________________________                                    

As is appreciated from the results shown in Table 2, thequinolinecarboxylic acid derivatives of the resent invention exhibited apotent stimulating activity on 5-HT₄ receptor.

Experiment 2.

Effect on inhibition of 5-HT₄ receptor-binding

The effect on inhibition of 5-HT₄ receptor-binding of thequinolinecarboxylic acid derivatives of the present invention wasexamined according to the method described in GROSSMAN et al., Br. J.Pharmacol., 109, 618 (1993).

Method

1. Membrane preparation (5-HT₄ receptor)

The longitudinal muscle strip from guinea pig was homogenized in 0.32Msucrose with a Teflon-glass homogenizer. After centrifugation at 900 Gfor 10 minutes, the upper fraction of lipids and precipitates wasdiscarded and the supernatant was centrifuged at 100,000 G (48,000 rpm)for an hour. The pellet was resuspended in 50 mM HEPES buffer. Afterincubation at 37° C. for 30 minutes, the suspension was centrifuged at48,000 rpm for 20 minutes. The pellet was suspended in HEPES buffersupplemented with 10⁻⁶ M pargyline and 0.1% ascorbic acid. Thesuspension was used for the binding assay.

2. Assay for the inhibition of 5-HT4 receptor-binding

The membrane preparation was incubated at 25° C. for 30 minutes,together with 0.1 nM of ³ H!GR113808 (Amersham, selective 5-HT₄ receptorbinding agent) and the sample compound at the final concentration of 1.0ml in the sample compound. Non-specific binding was defined as thattaken in the presence of 3×10⁻⁵ M 5-HT. B/F separation was performedthrough GF/B filter treated with 0.1% polyethyleneimine, using a cellharvester. Washing was performed once.

3. Compounds assayed

Each of the sample compounds and cisapride were dissolved in DMSO andeach solution was provided for the assay at the final concentration of1% DMSO.

Results

The IC₅₀, value of 50% inhibition, of each of the sample compounds andcisapride in the binding inhibition assay was determined in accordancewith the computer program of IC₅₀ instructed by Windows-origin (MicrocalSoftware).

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Inhibition of 5-HT.sub.4 receptor-binding                                     ( .sup.3 H!GR113808 binding in guinea pig)                                                  Ileum (n = 3)                                                                 IC.sub.50 (nM)                                                  ______________________________________                                        This Invention:                                                               Compound      5     42.19 ± 6.29                                                         20     78.14 ± 14.52                                                       11    68.70 ± 7.32                                                         10     78.50 ± 14.63                                         Comparison:                                                                   Cisapride       97.47 ± 9.17                                               ______________________________________                                    

As is noted from the results shown in Table 3, the quinolinecarboxylicacid derivatives of the present invention exhibit a potent activity forinhibiting binding to 5-HT₄ receptor in the longitudinal muscular stripof guinea pig ileum.

Experiment 3

Selectivity for receptors

The selectivity for receptors of the quinolinecarboxylic acidderivatives of the present invention was examined by the followingmethod.

Method

1) Dopamine 2 receptor

The affinity to dopamine 2 (D₂) receptor was examined according to themethod described in MALMBERG, A. et al., Mol Pharmacol., 43, 749-754(1993).

The affinity for D₂ receptor was studied in terms of the inhibition of ³H! raclopride (Daiichi Kagaku Yakuhin Co.) binding to rat striatalmembrane. The rat striatum was homogenized in 50 mM Tris hydrochloridebuffer (pH 7.4) followed by centrifugation at 48,000 G. The pellet waswashed once with Tris hydrochloride buffer. Then the pellet wassuspended in 50 mM Tris hydrochloride buffer (containing 120 mM NaCl, 5mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, pH 7.4) and provided for use as themembrane preparation. The membrane preparation (0.5 mg protein/ml) wasreacted with 1 nM 3H! raclopride at 25° C. for 60 minutes. After thereaction, the membrane was caught by a harvester. Non-specific bindingwas defined as that taken in the presence of 10 μM haloperidol.

2) Serotonin 3 receptor

The affinity for serotonin 3 receptor was examined by the methoddescribed in KILPATRICK, G. J. et al., Nature (London), 330, 746-748(1987).

The affinity to serotonin 3 (5-HT₃) was examined in terms of inhibitionof ³ H!GR65630 binding (Daiichi Kagaku Yakuhin Co.) binding to ratcerebral cortex membrane. The rat cerebral cortex was homogenized in 50mM Tris hydrochloride buffer (pH 7.4) followed by centrifugation at48,000 G. The precipitates were washed once with Tris hydrochloridebuffer. Then the precipitates were suspended in 50 mM Tris hydrochloridebuffer and provided for use as the membrane preparation. The membranepreparation was reacted with 0.2 nM ³ H!GR65630 at 37° C. for 30minutes. After the reaction, the membrane was caught by a harvester.Non-specific binding was defined as the binding taken in the presence of1 μM zacopride.

3) Serotonin _(1A) receptor

The affinity to serotonin _(1A) (5-HT_(1A)) receptor was examined by themethod described in SCHLEGEL, J. R. et al., Biochem. Pharmacol., 12,1943-1949 (1986).

The affinity to serotonin _(1A) (5-HT_(1A)) was examined in terms ofinhibition of ³ H! 8-OH-DPAT (Daiichi Kagaku Yakuhin Co.) binding to ratcerebral cortex membrane. The rat cerebral cortex was homogenized in 50mM Tris hydrochloride buffer (pH 7.4) followed by centrifugation at48,000 G.

The pellet was washed once with Tris hydrochloride buffer. Then thepellet was suspended in 50 mM Tris hydrochloride buffer (supplementedwith 0.01 mM pargyline and 0.1% ascorbic acid, pH 7.7) and provided foruse as the membrane preparation. The membrane specimen was reacted with1 nM ³ H! 8-OH-DPAT at 37° C. for 15 minutes. After the reaction, themembrane was caught by a harvester. Non-specific binding was defined asthat taken in the presence of 10 μM 5-HT.

4) Compounds assayed

Each of the sample compounds and cisapride were dissolved in DMSO andeach solution was provided for the assay at the final concentration of1% DMSO.

Results

The IC₅₀ value of each of the sample compounds and cisapride in thebinding inhibition assay was determined in accordance with the computerprogram of IC50 instructed by Windows-origin.

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Selectivity for receptors                                                               Compound of This                                                              Invention        Comparison                                                   5     10      11      20   Cisapride                                ______________________________________                                        Dopamine D.sub.2 receptor                                                                 --      --      --    --   107.5                                  antagonizing action                                                           (IC.sub.50, nM)                                                               5-HT.sub.3 receptor                                                                       977     811     423   509  97.7                                   antagonizing action                                                           (IC.sub.50, nM)                                                               5-HT.sub.1A receptor                                                                      --      --      --    --   64.7                                   antagonizing action                                                           (IC.sub.50, nM)                                                               ______________________________________                                         -: no activity in 10 μM                                               

The results shown in Table 4 reveal that the quinolinecarboxylic acidderivatives of the present invention do not show any substantialantagonizing activity for any of dopamine D₂ receptor, 5-HT₃ receptorand 5-HT_(1A) receptor.

Experiment 4

Gastrointestinal motor activity

The gastrointestinal motor-enhancing activity by the quinolinecarboxylicacid derivatives of the present invention was examined by a modificationof the method described in YOSHIDA, N. and ITO, T., The Journal ofPharmacology and Experimental Therapeutics, 257, 781-787 (1991):"AS-4370, a new gastrokinetic agent, enhances upper gastrointestinalmotor activity in conscious dogs".

Method

Model dog was prepared and the assay was performed, by a modification ofthe method by Yoshida et al. For the assay, female beagle dog was used.The animal was anesthetized with pentobarbital (30 mg/kg, i.v.) and theabdominal cavity was opened. Extraluminal force transducers (sensor tomeasure contraction; Star Medical Co., Model F-12IS) were sutured ontofive (5) sites, i.e., the gastric antrum, 3 cm proximal to the pyloricring, the duodenum, 5 cm distal to the pyloric ring, the jejunum, 70 cmdistal to the pyloric ring, the ileum, 5 cm proximal to the ileum-colonjunction, and the colon, 5 cm distal to the ileum-colon junction. Thelead wires of these force transducers were taken out of the abdominalcavity and then brought out through a skin incision made between thescapulae, at which a connector was connected. After the operation, ajacket protector was placed on the dog to protect the connector.Measurement of the gastrointestinal motor activity started from twoweeks after the operation. For ad libitum measurement, a telemeter(electrowave data transmitter; Star Medical Co., Model DAT-80T) wasconnected with the connector to determine the contractive motility ateach site of the gastrointestinal tract. The data was stored in acomputer (NEC, Model PC9801FA) via a telemeter (receiver; Star MedicalCo., Model DAT-80A) for analysis.

The drug (vehicle, cisapride and Compound 5 of the present invention)was administered intravenously through the forepaw two hours afterfeeding (1116 kcal; Oriental Yeast Co.).

Cisapride and Compound 5 of the present invention were dissolved in 0.5%dl-lactate solution, respectively. For control, 0.5% dl-lactate solutionwas employed as the vehicle.

Results

The gastrointestinal motility was processed by the computer every 15minutes in terms of motility index (M.I., g-min). The motor index givenby the processing system corresponded to the area surrounded by thecontraction wave and base line drawn by the computer on the display.Software for analysis: Software for analysis of organ motility ESC-820,Star Medical Co.).

With respect to the gastric antrum, the duodenum and the jejunum, M.I.is expressed by the mean value of the motility index for the 15-minuteperiod for the enhancing activity of motility before and 1 hour afteradministration, i.e., (total sum of M.I. (%) between 0 and 1 hour)/4.With respect to the ileum and the colon, M.I. is expressed by the meanvalue for the 15-minute period for the enhancing activity of motilitybefore and 0.5 hour after administration, i.e., (total sum of M.I. (%)between 0 and 0.5 hour)/2. In this case, M.I. (%) was calculated bydesignating as 100% the mean value for the 15-minute period 30 minutesbefore administration.

The results are shown in FIG. 1. As is evident from FIG. 1, thequinolinecarboxylic acid derivative of the present invention showed apotent activity particularly on the motility in the gastric antrum andthe ileum.

Industrial Applicability

The quinolinecarboxylic acid derivative or its pharmaceuticallyacceptable salt of the present invention acts on a serotonin 4 receptorand thereby showing a serotonin-like stimulating activity on serotonin 4receptor. More specifically, the compounds of the present inventionexhibit an action of enhancing the gastrointestinal motor functions toimprove the gastrointestinal conditions such as heartburn, anorexia,bowel pain, abdominal distension, etc., accompanied by chronicgastritis, diabetes mellitus or postoperative gastro-paresis, and arethus effective for the treatment of gastro-esophagal reflux, intestinalpseudo-obstruction and constipation.

We claim:
 1. A quniolinecarboxylic acid derivative represented byformula (A): ##STR29## wherein: X represents an oxygen atom or iminogroup;m represents 0 or an integer of 1 to 6;and, A represents analkenyl group having 2-6 carbon atoms, an alkynyl group having 2-6carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, hydroxygroup, an alkoxy group having 1-6 carbon atoms, an acyloxy group having2-8 carbon atoms, an alkoxyalkoxy group having 2-8 carbon atoms, a mono-or di-alkylamino group having 1-6 carbon atoms, an alkythio group having1-6 carbon atoms, an alkylsulfinyl group having 1-6 carbon atoms, analkylsulfonyl group having 1-6 carbon atoms, a phenylsulphonyl group,tolylsulfonyl group or naphthylsulfonyl group, a phenoxy group, tolyloxygroup or naphthyloxy group, morpholinyl group, piperidyl group,tetrahydropyranyl group, an alkoxycarbonyl group having 2-7 carbonatoms, carboxyl group, an alkanoyl group having 2-8 carbons atoms, cyanogroup or carbamoyl group; or a pharmaceutically acceptable salt thereof.2. A quinolinecarboxylic acid derivative or a pharmaceuticallyacceptable salt thereof according to claim 1, which is represented byformula (B): ##STR30## wherein X represents an oxygen atom or iminogroup; n represents an integer of 1 to 6; andY represents hydroxy group,an alkoxy group having 1-6 carbon atoms, an alkanoyl group having 2-8carbon atoms, an alkoxycarbonyl group having 2-7 carbon atoms ormorpholinyl group.
 3. A quniolinecarboxylic acid derivative or apharmaceutically acceptable salt thereof according to claim 1, which isrepresented by formula (C): ##STR31## wherein Z representshydroxymethyl, methoxy, ethoxy or morpholino group.
 4. A pharmaceuticalcomposition comprising as an effective ingredient a quinolinecarboxylicacid derivative or pharmaceutically acceptable salt thereof according toclaim 1 and a pharmaceutically acceptable carrier, wherein saideffective ingredient is added in an amount effective for stimulating aserotonin 4 receptor.
 5. A method for stimulating a serotonin 4 receptorwhich comprises administering to human an effective dose of aquinolinecarboxylic acid derivative or a pharmaceutically acceptablesalt thereof according to claim
 1. 6. The quinolinecarboxylic acidderivative or a pharmaceutically acceptable salt thereof according toclaim 1, which is endo-N-(8-(3-hydroxypropyl)-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide.